Statins in Children With Type 1 Diabetes and Hypercholesterolemia

• Sponsor: Nemours Children's Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT01236365
• Collaborator: Pfizer (Industry), Medtronic (Industry), Quest Diagnostics-Nichols Insitute (Industry)
• Enrollment: 42
• Locations: 5
• Arms: 2
• Duration (Months): 49
• Patients Per Site: 8.4
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

Children with type1 diabetes (T1DM) have increased risk for cardiovascular disease (CVD) due to chronic increase in the blood sugars and inflammation. If there is also increased in cholesterol, it creates a highly abnormal environment not fully corrected by improved control of the blood sugars. CVD remains the principal risk of mortality in T1DM, and its prevention and treatment, compelling in children. This grant proposal encompasses 3 separate, yet interrelated projects addressing different aspects of CVD risk in children with T1DM. Project #1: a randomized controlled trial on the safety and efficacy of a class of drugs called "statins", which lower bad cholesterol in the body, in children with diabetes and elevated bad cholesterol. We will measure changes in concentration of blood inflammatory markers and for the 1st time, correlate levels of these markers with changes in blood sugar as measured by continuous glucose sensors, instruments that measure the blood sugar continuously through a small needle under the skin. Project #2: is a laboratory study to investigate the genetics and concentration of key molecules that participate in the inflammatory cascade and atheromatous plaque formation that causes CVD. Expression levels in children with T1DM will be compared with those in healthy controls for the 1st time. Project #3: examines the use of abdominal aortic MRI to measure damage to the arteries in children with T1DM and healthy age-matched controls. The results of these studies will likely provide important new data on the use of statins in children with diabetes.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus, Insulin-Dependent; Hypercholesterolemia	Drug: Atorvastatin; Drug: Atorvastatin Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 42 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Statins in Children With Type 1 Diabetes: Effects on Metabolism, Inflammation and Endothelial Function
• Study Start Date: Oct 1, 2010
• Actual Primary Completion Date: Oct 1, 2013
• Actual Study Completion Date: Nov 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Atorvastatin	Drug: Atorvastatin; 10 or 20 mg daily; Other Names: Lipitor
Placebo Comparator: Placebo	Drug: Atorvastatin Placebo; 10 or 20 mg daily

Outcome Measures

Primary Outcome Measures

1. LDL-C Levels Assessed at Randomization and 6 Months [Randomization and 6 months]

   To assess if the use of statins in children with type 1 DM is safe, improves measures of LDL-C. Subjects will have a physical exam, laboratories, nutritional counseling and moderate aerobic exercise recommended. Diabetes management will be intensified. At 3 months fasting lipoprotein fractions (ion mobility)re-drawn and if LDL-C >100mg/dl patients will be randomized to treatment with statins or placebo for 6 months, randomization stratified by BP and microalbuminuria, duration of diabetes and HgA1C. At 1 month safety labs will be repeated and blood withdrawn again at 3 and 6 months from baseline.

2. Hs-CRP Levels Assessed at Randomization and 6 Months [Randomization and 6 months]

   To assess if the use of statins in children with type 1 DM decreases the concentration of inflammatory markers.

Secondary Outcome Measures

1. MAGE [Randomization and 6 months]

   Mean amplitude of glycemic excursion (MAGE) with continuous glucose monitoring (CGM - IPro®, Medtronic Minimed) worn blindly for 6d to assess glucose variability

2. RAGE [Randomization and 6 months]

   Receptor for Advanced Glycation End Products

3. Descending Aortic Strain [Randomization]

   Subclinical atherosclerosis and arterial stiffness of abdominal aortic MRI

Eligibility Criteria

Criteria

• Ages Eligible for Study: 10 Years to 20 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:Project 1

• T1DM diagnosed clinically for > 1 year

• any HbA1C

• on stable insulin therapy

• Ages: 10 - 20 years

• both genders

• BMI < 85th percentile

• Fasting LDL-C>100mg/dl

• Normal thyroid function

Inclusion Criteria:Projects 2 and 3

• T1DM diagnosed clinically for > 3 year

• HbA1C > 8%

• on stable insulin therapy

• Ages: 12- 20 years

• both genders

• BMI < 85th percentile

• Fasting LDL-C>100mg/dl

• Normal thyroid function

Exclusion Criteria:Projects 1,2 and 3

• Severe dyslipidemia (LDL-C >160, TG > 400 mg/dl)

• Smoking

• Pregnancy

• Current use of anti-inflammatory or immunomodulatory drugs, lipid lowering, antidiabetic drugs

• Patients with hypertension and/or microalbuminuria will be allowed using balanced randomization and standardized treatment

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Alfred I duPont Hospital	Wilmington	Delaware	United States
2	Nemours Children's Clinic	Jacksonville	Florida	United States	32207
3	Nemours Children's Clinic	Orlando	Florida	United States
4	Nemours Children's Clinic	Pensacola	Florida	United States	32504
5	Nemours Children's Clinic-Jefferson	Philadelphia	Pennsylvania	United States	19107

Sponsors and Collaborators

• Nemours Children's Clinic
• Pfizer
• Medtronic
• Quest Diagnostics-Nichols Insitute

Investigators

• Principal Investigator: Nelly Mauras, MD, Nemours Children's Clinic 807 Children's Way Jacksonville, Florida 32207

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Nelly Mauras, Chief, Division of Endocrinology, Diabetes & Metabolism, Nemours Children's Clinic
• ClinicalTrials.gov Identifier: NCT01236365
• Other Study ID Numbers: IRB# 185500
• First Posted: Nov 8, 2010
• Last Update Posted: Jun 25, 2019
• Last Verified: Jun 1, 2019

• Keywords provided by Nelly Mauras, Chief, Division of Endocrinology, Diabetes & Metabolism, Nemours Children's Clinic: Type 1 diabetes; Children; Statins; Hypercholesterolemia; Lipoproteins; C reactive protein; Continuous glucose monitors; Adolescence; Abdominal magnetic resonance imaging; Toll like receptors; Receptors of advanced glycation end products; Nutrition
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1; Hypercholesterolemia; Atorvastatin

Study Results

Participant Flow

Arm/Group Title	Atorvastatin	Placebo
Arm/Group Description	Atorvastatin: 10 or 20 mg daily	Placebo: 10 or 20 mg daily
Period Title: Overall Study
STARTED	21	21
COMPLETED	19	19
NOT COMPLETED	2	2

Baseline Characteristics

Arm/Group Title	Atorvastatin	Placebo	Total
Arm/Group Description	Atorvastatin: 10 or 20 mg daily	Atorvastatin Placebo: 10 or 20 mg daily	Total of all reporting groups
Overall Participants	21	21	42
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	14.9 (2.2)	15.4 (2.7)	15.1 (2.4)
Sex: Female, Male (Count of Participants)
Female	11 52.4%	9 42.9%	20 47.6%
Male	10 47.6%	12 57.1%	22 52.4%
Race/Ethnicity, Customized (participants) [Number]
non-Hispanic white	17 81%	14 66.7%	31 73.8%
Other	4 19%	7 33.3%	11 26.2%
Region of Enrollment (participants) [Number]
United States	21 100%	21 100%	42 100%

Outcome Measures

1. Primary Outcome

Title	LDL-C Levels Assessed at Randomization and 6 Months
Description	To assess if the use of statins in children with type 1 DM is safe, improves measures of LDL-C. Subjects will have a physical exam, laboratories, nutritional counseling and moderate aerobic exercise recommended. Diabetes management will be intensified. At 3 months fasting lipoprotein fractions (ion mobility)re-drawn and if LDL-C >100mg/dl patients will be randomized to treatment with statins or placebo for 6 months, randomization stratified by BP and microalbuminuria, duration of diabetes and HgA1C. At 1 month safety labs will be repeated and blood withdrawn again at 3 and 6 months from baseline.
Time Frame	Randomization and 6 months

Outcome Measure Data

Analysis Population Description

Project #1. Adjusted for age, gender and ISS (Insulin sensitivity score)

Arm/Group Title	Atorvastatin LDL-C at Randomization	Atorvastatin LDL-C at 6 Months	Placebo LDL-C at Randomization	Placebo LDL-C at 6 Months
Arm/Group Description
Measure Participants	19	19	19	19
Mean (Standard Error) [mg/dL]	128 (4)	87 (5)	126 (5)	133 (8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Atorvastatin LDL-C at Randomization, Atorvastatin LDL-C at 6 Months
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Change in LDL-C between Atorvastatin and Placebo
	Method	Mixed Models Analysis
	Comments

2. Primary Outcome

Title	Hs-CRP Levels Assessed at Randomization and 6 Months
Description	To assess if the use of statins in children with type 1 DM decreases the concentration of inflammatory markers.
Time Frame	Randomization and 6 months

Outcome Measure Data

Analysis Population Description

Project #1

Arm/Group Title	Atorvastatin hsCRP at Randomization	Atorvastatin hsCRP at 6 Months	Placebo hsCRP at Randomization	Placebo hsCRP at 6 Months
Arm/Group Description
Measure Participants	19	19	19	19
Median (Inter-Quartile Range) [mg/dL]	0.363	0.419	0.248	0.446

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Atorvastatin LDL-C at Randomization, Atorvastatin LDL-C at 6 Months, Placebo LDL-C at Randomization, Placebo LDL-C at 6 Months
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.913
	Comments	Change in hsCRP (6months minus 0months) between Atorvastatin and Placebo
	Method	Wilcoxon (Mann-Whitney)
	Comments

3. Secondary Outcome

Title	MAGE
Description	Mean amplitude of glycemic excursion (MAGE) with continuous glucose monitoring (CGM - IPro®, Medtronic Minimed) worn blindly for 6d to assess glucose variability
Time Frame	Randomization and 6 months

Outcome Measure Data

Analysis Population Description

Project #1. 4 Atorvastatin and 8 Placebo Subjects did not complete their CGM at 6months.

Arm/Group Title	Atorvastatin MAGE at Randomization	Atorvastatin MAGE at 6 Months	Placebo MAGE at Randomization	Placebo MAGE at 6 Months
Arm/Group Description
Measure Participants	19	15	19	11
Mean (Standard Error) [mg/dL]	150 (9)	156 (13)	156 (6)	152 (8)

4. Secondary Outcome

Title	RAGE
Description	Receptor for Advanced Glycation End Products
Time Frame	Randomization and 6 months

Outcome Measure Data

Analysis Population Description

Project #2. Study Subjects were given the option to participate in the Project #2 genetic substudy; 9 Atorvastatin and 12 Placebo Subjects participated in Project #2. 1 Atorvastatin and 1 Placebo Subject did not complete the 6 month genetic test.

Arm/Group Title	Atorvastatin LDL-C at Randomization	Atorvastatin LDL-C at 6 Months	Placebo LDL-C at Randomization	Placebo LDL-C at 6 Months
Arm/Group Description
Measure Participants	9	8	12	11
Mean (Standard Error) [pg/mL]	49 (11)	35 (5)	50 (7)	58 (17)

5. Secondary Outcome

Title	Descending Aortic Strain
Description	Subclinical atherosclerosis and arterial stiffness of abdominal aortic MRI
Time Frame	Randomization

Outcome Measure Data

Analysis Population Description

Project #3. Study Subjects were given the option to participate in the Project #3 MRI substudy; 11 Atorvastatin and 8 Placebo Subjects participated in Project #3.

Arm/Group Title	Atorvastatin at Randomization	Placebo at Randomization
Arm/Group Description
Measure Participants	11	8
Mean (Standard Deviation) [percent area change]	27.2 (6.4)	29 (8.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Atorvastatin LDL-C at Randomization
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.09
	Comments
	Method	t-test, 2 sided
	Comments

Adverse Events

Arm/Group Title	Atorvastatin		Placebo
Arm/Group Description	Atorvastatin: 10 or 20 mg daily		Atorvastatin Placebo: 10 or 20 mg daily
All Cause Mortality
	Atorvastatin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Atorvastatin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/21 (4.8%)		0/21 (0%)
Musculoskeletal and connective tissue disorders
Fall	1/21 (4.8%)	1	0/21 (0%)	0
Other (Not Including Serious) Adverse Events
	Atorvastatin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/21 (52.4%)		7/21 (33.3%)
Ear and labyrinth disorders
Sinus Symptoms	2/21 (9.5%)	2	2/21 (9.5%)	2
Gastrointestinal disorders
Stomach Discomfort	2/21 (9.5%)	2	3/21 (14.3%)	3
Acid Reflux	1/21 (4.8%)	1	1/21 (4.8%)	1
Hepatobiliary disorders
Abnormal Chemistry Labs	1/21 (4.8%)	1	1/21 (4.8%)	2
Infections and infestations
Throat Infection	2/21 (9.5%)	2	1/21 (4.8%)	3
Musculoskeletal and connective tissue disorders
Costochondritis	1/21 (4.8%)	1	1/21 (4.8%)	2
Lower Extremity Cramping	2/21 (9.5%)	2	2/21 (9.5%)	2
Hand Fracture	0/21 (0%)	0	1/21 (4.8%)	1
Elevated CK Blood Level	1/21 (4.8%)	2	0/21 (0%)	0
Nervous system disorders
Headache	0/21 (0%)	0	1/21 (4.8%)	1
Hypoglycemic Seizure	1/21 (4.8%)	1	0/21 (0%)	0
Renal and urinary disorders
Hematuria with Flank Pain	1/21 (4.8%)	2	0/21 (0%)	0
Reproductive system and breast disorders
Ovarian Cyst	0/21 (0%)	0	1/21 (4.8%)	1
Skin and subcutaneous tissue disorders
Cut/Laceration	1/21 (4.8%)	1	2/21 (9.5%)	2
Rash	2/21 (9.5%)	2	1/21 (4.8%)	1
Acne	1/21 (4.8%)	1	0/21 (0%)	0
Social circumstances
Fatigue	2/21 (9.5%)	2	0/21 (0%)	0

Limitations/Caveats

[Not Specified]

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.