Atheroma Reduction With Chloroquine in Patients With the Metabolic Syndrome (ARCH-MS)

• Sponsor: Washington University School of Medicine (Other)
• Overall Status: Completed
• CT.gov ID: NCT00455403
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH), Singulex (Industry)
• Enrollment: 357
• Location: 1
• Arms: 2
• Actual Duration (Months): 44
• Patients Per Site Per Month: 8.1

Study Details

Study Description

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 long-term effectiveness of chloroquine, a protein-activation medication, at reducing the progression of atherosclerosis in patients with the metabolic syndrome.

Sub-study: Vascular endothelial growth factor(VEGF)and Cardiometabolic Risk, The purpose is to determine if the association of VEGF with atherosclerosis indicates that it should be a marker of the disorder.

Condition or Disease	Intervention/Treatment	Phase
Metabolic Syndrome X; Overweight; Hypertension; Dyslipidemias; Prediabetic State	Drug: Chloroquine; Drug: Placebo Comparator	N/A

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 examine the effect of long-term treatment with low doses of chloroquine on atherosclerosis in people with metabolic syndrome.

At a baseline study visit, participants will undergo an ultrasound of the neck to evaluate carotid artery intima-media thickness (IMT) and MRI to evaluate plaque composition. In addition, blood will be collected for laboratory testing and blood pressure will be measured. Participants will then be randomly assigned to receive either placebo or chloroquine. Study visits will occur every 3 months for 1 year. At each visit, blood pressure will be measured and blood will be collected. At Months 6 and 12, a repeat ultrasound will be performed. At month 12 a repeat carotid MRI is performed. Participants will attend one follow-up visit at Month 24 and will undergo a final ultrasound.

Sub-Study: VEGF and Cardiometabolic Risk, (This is an observational, case-study of existing baseline plasma and carotid intimal-medial thickness measurements) VEGF is also closely linked to vascular disease. From cell culture and animal models it is known that VEGF is increased in atherosclerotic lesions. It is controversial whether that relationship is causative or reparative. Both pro- and anti-VEGF therapies have been proposed for atherosclerosis. However, the association of VEGF with atherosclerosis indicates that it should be a marker of the disorder, which is the hypothesis we wish to test. No previous studies of circulating VEGF have been published.

Other markers may be related to vascular disease or VEGF in this dataset. Tumor necrosis factor (TNF)-alpha results in increased expression of VEGF and may be correlated positively with VEGF. By Erenna Technology testing, cardiac troponin I can be measured at levels much lower than current clinical assays and is expected to be elevated in ischemia but not necessarily in the stable vascular disease anticipated in our subjects. High sensitivity C-reactive protein (hsCRP)has been proposed as a marker for vascular disease that merits drug treatment in its own right and may also be correlated with VEGF and vascular disease. However, currently the relationship between hsCRP and vascular disease is not completely clear.

For this preliminary VEGF study observational data from the baseline only will be studied. Baseline testing includes carotid artery intimal-medial thickness, carotid MRI, lipid panel, complete blood count, comprehensive metabolic chemistry panel, Thyroid-stimulating hormone (TSH) and glucose tolerance test with plasma insulin and glucose responses. Plasma collected at baseline (approximately 1 ml) will be transferred to Singulex on dry ice. Samples will be coded but will not contain patient identifiers. Erenna Technology assays will be done for VEGF-A, cardiac troponin I,TNF-alpha, interleukin-6, interleukin-17A, and other cytokines at Singulex. This method utilizes single-photon counting of visible light to improve assay sensitivity. Separately, Washington University's Core Lab for Clinical Studies (CLCS) will determine hsCRP.

Study Design

• Study Type: Interventional
• Actual Enrollment: 357 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Genotoxic Stress, Atherosclerosis, and Metabolic Syndrome- Aim 3
• Actual Study Start Date: Apr 1, 2006
• Actual Primary Completion Date: Dec 1, 2009
• Actual Study Completion Date: Dec 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Chloroquine Subjects Participants will receive 80 mg of chloroquine on a daily basis.	Drug: Chloroquine; One tablet of 80 mg of chloroquine on a daily basis for 12 months followed by 12 months off drug with 1 visit at month 24; Other Names: Arlen
Placebo Comparator: Placebo Subjects Participants will receive a placebo comparator tablet on a daily basis.	Drug: Placebo Comparator; Chloroquine Placebo tablet daily for 12 months followed by 12 months off drug with 1 visit at month 24; Other Names: placebo

Outcome Measures

Primary Outcome Measures

1. Change in Carotid Intima-media Thickness From Baseline to Year 1 [Measured at baseline and year 1]

   A noninvasive predictor of cardiovascular events, Carotid artery intima-media thickness (CIMT) was measured from B-mode images by a single sonographer using standard approaches

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Diagnosis of metabolic syndrome, as determined by at least three of the following five criteria:

1. Elevated fasting triglyceride level greater than 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 (greater than or equal to 130/85 mm Hg and less than or equal to 160/100 mm Hg) untreated; or hypertension controlled (less than or equal to 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 level greater than or equal to 100 mg/dL and less than or equal to 126 mg/dL

• Willing to use acceptable form of birth control

• 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

Exclusion Criteria:

• Prior travel treatment with chloroquine or hydroxychloroquine as follows:

1. Any exposure in the past 2 years

2. More than 30 days of therapy if exposure was between 2 and 5 years ago

3. More than 90 days of therapy if exposure was between 5 and 10 years ago

4. More than 6 months of therapy if exposure was 10 to 20 years ago

5. More than 1 year of therapy if exposure was 20 to 30 years ago

6. No limit if last exposure was more than 30 years ago (e.g., during the Vietnam conflict)

• Morbid obesity (body mass index [BMI] greater than 45)

• Coronary artery disease or other vascular disease

• History of stroke

• Significant kidney disease (estimated glomerular filtration rate (eGFR)less than 60 mL/min/1.73 m2)

• 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.

• Receiving any of the following lipid lowering medications: niacin, fibrates, or fish oils greater than 1 gram

• Uncontrolled hypertension (blood pressure greater than or equal to 150/90) at baseline visit.

• Need for daily over the counter medications, or currently taking cimetidine or greater than 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. Patients taking greater than 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

• Auditory disease or hearing loss; patients 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Washington University School of Medicine	Saint Louis	Missouri	United States	63110

Sponsors and Collaborators

• Washington University School of Medicine
• National Heart, Lung, and Blood Institute (NHLBI)
• Singulex

Investigators

• Principal Investigator: Clay F. Semenkovich, MD, Washington University School of Medicine

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• click here for Washington University Research Participant Registry

Publications

None provided.

• Responsible Party: Washington University School of Medicine
• ClinicalTrials.gov Identifier: NCT00455403
• Other Study ID Numbers: 201110238(3); P50HL083762
• First Posted: Apr 3, 2007
• Last Update Posted: Dec 15, 2021
• Last Verified: Dec 1, 2021

• Keywords provided by Washington University School of Medicine: Metabolic Syndrome; Atherosclerosis
• Additional relevant MeSH terms: Metabolic Syndrome; Dyslipidemias; Prediabetic State; Syndrome; Overweight; Chloroquine

Study Results

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.
Pre-assignment Detail	241 participants screen failed

Arm/Group Title	Chloroquine Subjects	Placebo Subjects
Arm/Group Description	Participants will receive 80 mg of chloroquine on a daily basis. Chloroquine: One tablet of 80 mg of chloroquine on a daily basis for 12 months followed by 12 months off drug with 1 visit at month 24	Participants will receive a placebo comparator tablet on a daily basis. Placebo Comparator: Chloroquine Placebo tablet daily for 12 months followed by 12 months off drug with 1 visit at month 24
Period Title: Overall Study
STARTED	59	57
COMPLETED	56	51
NOT COMPLETED	3	6

Baseline Characteristics

Arm/Group Title	Chloroquine Subjects	Placebo Subjects	Total
Arm/Group Description	Participants will receive 80 mg of chloroquine on a daily basis. Chloroquine: One tablet of 80 mg of chloroquine on a daily basis for 12 months followed by 12 months off drug with 1 visit at month 24	Participants will receive a placebo comparator tablet on a daily basis. Placebo Comparator: Chloroquine Placebo tablet daily for 12 months followed by 12 months off drug with 1 visit at month 24	Total of all reporting groups
Overall Participants	59	57	116
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	51 86.4%	53 93%	104 89.7%
>=65 years	8 13.6%	4 7%	12 10.3%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55 (12)	55 (9)	55 (12)
Sex: Female, Male (Count of Participants)
Female	44 74.6%	33 57.9%	77 66.4%
Male	15 25.4%	24 42.1%	39 33.6%

Outcome Measures

1. Primary Outcome

Title	Change in Carotid Intima-media Thickness From Baseline to Year 1
Description	A noninvasive predictor of cardiovascular events, Carotid artery intima-media thickness (CIMT) was measured from B-mode images by a single sonographer using standard approaches
Time Frame	Measured at baseline and year 1

Outcome Measure Data

Analysis Population Description

Intent to treat

Arm/Group Title	Chloroquine Subjects	Placebo Subjects
Arm/Group Description	Participants will receive 80 mg of chloroquine on a daily basis. Chloroquine: One tablet of 80 mg of chloroquine on a daily basis for 12 months followed by 12 months off drug with 1 visit at month 24	Participants will receive a placebo comparator tablet on a daily basis. Placebo Comparator: Chloroquine Placebo tablet daily for 12 months followed by 12 months off drug with 1 visit at month 24
Measure Participants	59	57
Baseline	0.766 (0.17)	0.765 (0.13)
Year 1	0.758 (0.16)	0.768 (0.11)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Chloroquine Subjects, Placebo Subjects
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.7279
	Comments	Applies to row Title "year 1"
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.010
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	applies to row title "year 1"

Adverse Events

Time Frame	2 years 6 months
Arm/Group Title	Chloroquine Subjects		Placebo Subjects
Arm/Group Description	Participants will receive 80 mg of chloroquine on a daily basis. Chloroquine: One tablet of 80 mg of chloroquine on a daily basis for 12 months followed by 12 months off drug with 1 visit at month 24		Participants will receive a placebo comparator tablet on a daily basis. Placebo Comparator: Chloroquine Placebo tablet daily for 12 months followed by 12 months off drug with 1 visit at month 24
All Cause Mortality
	Chloroquine Subjects		Placebo Subjects
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/59 (0%)		0/57 (0%)
Serious Adverse Events
	Chloroquine Subjects		Placebo Subjects
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/59 (8.5%)		2/57 (3.5%)
Gastrointestinal disorders
acute appendicitis	1/59 (1.7%)	1	0/57 (0%)	0
Infections and infestations
cutaneous staphylococcus infection	1/59 (1.7%)	1	0/57 (0%)	0
positive PPD	1/59 (1.7%)	1	0/57 (0%)	0
Nervous system disorders
transverse myelitis	1/59 (1.7%)	1	0/57 (0%)	0
Renal and urinary disorders
Prostate Cancer	0/59 (0%)	0	1/57 (1.8%)	1
Surgical and medical procedures
Right Knee Replacement	0/59 (0%)	0	1/57 (1.8%)	1
carotid endarterectomy	1/59 (1.7%)	1	0/57 (0%)	0
Other (Not Including Serious) Adverse Events
	Chloroquine Subjects		Placebo Subjects
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	39/59 (66.1%)		37/57 (64.9%)
Eye disorders
ocular	16/59 (27.1%)	51	10/57 (17.5%)	57
Immune system disorders
allergy/immunology	5/59 (8.5%)	51	10/57 (17.5%)	42
Infections and infestations
Infections	39/59 (66.1%)	51	37/57 (64.9%)	42
Nervous system disorders
CNS	5/59 (8.5%)	51	3/57 (5.3%)	57
Psychiatric disorders
Psychiatric	5/59 (8.5%)	51	6/57 (10.5%)	57

Limitations/Caveats

One limitation of the study is that it may have been underpowered to detect a difference in CIMT. Sample size estimates at the time of initiation of these studies were based on reports showing that insulin sensitizers had effects on CIMT with groups of 31-57 subjects, but subsequent work indicated the need for larger sample sizes.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.