The LANCET Trial: A Trial of Long-acting Insulin Injection to Reduce C-reactive Protein in Patients With Type 2 Diabetes

• Sponsor: Brigham and Women's Hospital (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00366301
• Collaborator: Sanofi (Industry)
• Enrollment: 500
• Location: 1
• Arms: 4
• Duration (Months): 32
• Patients Per Site Per Month: 15.6

Study Details

Study Description

Brief Summary

The purpose of this study, which is being conducted at 100 centers throughout the United States, is to determine whether Lantus, a long-acting insulin injection, either alone or in combination with metformin, is effective in reducing C-reactive protein (CRP) in adults with type 2 diabetes. CRP is a marker of chronic low-level inflammation, a new risk factor for diabetes, heart attack, stroke, and other cardiovascular events.

Condition or Disease	Intervention/Treatment	Phase
Type 2 Diabetes	Drug: Insulin glargine injection; Drug: metformin; Drug: Placebo pill	Phase 4

Detailed Description

Study Rationale

Low-grade systemic inflammation as indicated by elevated levels of C-reactive protein (CRP) is often present in patients with type 2 diabetes. Individuals with type 2 diabetes represent a vulnerable population in which cardiovascular event rates are high and among whom CRP reduction may have the greatest impact. While several classes of oral hypoglycemic agents have been shown to lower CRP, data are not available for newer formulations of long-acting insulins such as Lantus (insulin glargine injection) and no study has comprehensively evaluated the relative merit of insulin-providing versus insulin-sensitizing strategies for this purpose.

Investigational Plan

This is a multicenter, community-based, randomized 2x2 factorial trial of Lantus and metformin among patients with type 2 diabetes treated with either diet or oral monotherapy (other than metformin) only who have poor glycemic control and elevated CRP. The primary endpoint is change in CRP. Secondary endpoints include improvement in insulin sensitivity, glycemic control, blood lipids, as well as selected inflammatory and prothrombotic markers, and adipokine levels.

Limited data suggest that short-term insulin administration in patients with poorly controlled type 2 diabetes may lower CRP, but the benefit of CRP reduction that is unique to insulin therapy and independent of glycemic control per se remains uncertain. The insulin-sensitizing agent metformin, a mainstay of anti-diabetic therapy, has been shown to reduce macrovascular complications among patients with type 2 diabetes and, in some but not all randomized clinical trials, also has a modest CRP-lowering effect. This study is designed to assess whether the use of Lantus either alone or in combination with metformin lowers CRP over a 14-week treatment period.

Eligible men and women age 18 to 79 years with early diabetes on diet only or oral monotherapy with baseline HbA1c 7.0-10% and CRP greater than or equal to 2.0 mg/l will be randomized in a 2X2 factorial fashion as follows. First, participants will be assigned at random to open-label Lantus or no insulin. Then, within these two categories, subjects will be assigned at random to metformin or placebo. Thus, the four resultant treatment groups are Lantus injection and placebo pill, Lantus injection and metformin pill, metformin pill alone, and placebo pill alone. All patients will receive diet and exercise counseling.

This study design will permit testing of the overall effect of Lantus as well as the effect of combination therapy with metformin for CRP reduction at a targeted level of glycemic control (fingerstick fasting blood glucose < 110 mg/dl). All participants will be provided with a glucometer for fingerstick glucose testing calibrated to report plasma-referenced values.

Study Design

• Study Type: Interventional
• Actual Enrollment: 500 participants
• Allocation: Randomized
• Intervention Model: Factorial Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: The LANCET Trial: A Randomized Clinical Trial of Lantus for C-reactive Protein Reduction in Early Treatment of Type 2 Diabetes
• Study Start Date: Aug 1, 2006
• Actual Primary Completion Date: Apr 1, 2009
• Actual Study Completion Date: Apr 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo pill Placebo pill	Drug: Placebo pill; Up to 4 pills per day
Active Comparator: Metformin Pill Metformin pill	Drug: metformin; Up to 4 pils per day (2g per day) maximum
Active Comparator: Insulin Glargine plus placebo pill Insulin glargine plus placebo pill	Drug: Insulin glargine injection; Once daily for 14 weeks; Other Names: Lantus ; Drug: Placebo pill; Up to 4 pills per day
Active Comparator: Insulin Glargine plus metformin pill Insulin Glargine plus metformin pill	Drug: Insulin glargine injection; Once daily for 14 weeks; Other Names: Lantus ; Drug: metformin; Up to 4 pils per day (2g per day) maximum

Outcome Measures

Primary Outcome Measures

1. Percentage Reduction in C-reactive Protein (CRP) [14 weeks]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 79 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Men and women aged 18 to 79

• Type 2 diabetes, treated only by diet or oral drugs other than metformin

• HbA1c greater than or equal to 7% and less than or equal to 10%

• C-reactive protein greater than or equal to 2 mg/L

Exclusion Criteria:

• Baseline use of metformin or insulin

• Type 1 diabetes, history of ketoacidosis or positive anti-GAD antibody

• History of congestive heart failure requiring drug therapy

• Active liver disease

• Kidney impairment

• Recent initiation or change in dose of statins, fibric acid derivatives, angiotensin receptor blockers, nonsteroidal anti-inflammatory agents, or corticosteroids

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Brigham and Women's Hospital	Boston	Massachusetts	United States	02215

Sponsors and Collaborators

• Brigham and Women's Hospital
• Sanofi

Investigators

• Study Chair: Paul M Ridker, MD, MPH, Brigham and Women's Hospital
• Principal Investigator: Aruna Das Pradhan, MD, MPH, Brigham and Women's Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00366301
• Other Study ID Numbers: 2006-P-000823; Lantus_L_00833
• First Posted: Aug 21, 2006
• Last Update Posted: Nov 25, 2010
• Last Verified: Oct 1, 2010

• Keywords provided by , ,: type 2 diabetes; insulin; insulin injection; metformin; C-reactive protein; insulin sensitivity; glycemic control; inflammation
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Metformin; Insulin Glargine

Study Results

Participant Flow

Recruitment Details	Recruitment occurred at 73 US office-based practices between October 2006 and December 2008.
Pre-assignment Detail	Preenrollment evaluation comprised local laboratory testing of hsCRP,HbA1c, and safety parameters (ALT or AST and creatinine). Eligible participants were enrolled in a 2-week run-in. Ability to self-monitor fingerstick blood glucose and perform insulin injection was determined and evaluation for evidence of marked hyperglycemia was undertaken.

Arm/Group Title	Placebo Pill	Metformin Pill	Insulin Glargine Plus Placebo Pill	Insulin Glargine Plus Metformin Pill
Arm/Group Description	Placebo pill	Metformin pill	Insulin glargine plus placebo pill	Insulin Glargine plus metformin pill
Period Title: Overall Study
STARTED	124	126	126	124
Either 6W or 14W CRP Obtained	120	124	124	119
COMPLETED	116	120	122	116
NOT COMPLETED	8	6	4	8

Baseline Characteristics

Arm/Group Title	Placebo Pill	Metformin Pill	Insulin Glargine Plus Placebo Pill	Insulin Glargine Plus Metformin Pill	Total
Arm/Group Description	Placebo pill	Metformin pill	Insulin glargine plus placebo pill	Insulin Glargine plus metformin pill	Total of all reporting groups
Overall Participants	124	126	126	124	500
Age (years) [Mean (Standard Deviation) ]
Mean (SD)	54.0 (10.9)	53.8 (11.5)	53.8 (11.4)	54.0 (11.7)	53.9 (11.4)
Sex: Female, Male (Count of Participants)
Female	64 51.6%	68 54%	83 65.9%	66 53.2%	281 56.2%
Male	60 48.4%	58 46%	43 34.1%	58 46.8%	219 43.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	13 10.5%	4 3.2%	19 15.1%	17 13.7%	53 10.6%
Not Hispanic or Latino	110 88.7%	119 94.4%	104 82.5%	105 84.7%	438 87.6%
Unknown or Not Reported	1 0.8%	3 2.4%	3 2.4%	2 1.6%	9 1.8%
Race/Ethnicity, Customized (Number) [Number]
White	91 73.4%	88 69.8%	95 75.4%	91 73.4%	365 73%
African American	25 20.2%	34 27%	25 19.8%	24 19.4%	108 21.6%
Other	8 6.5%	4 3.2%	6 4.8%	9 7.3%	27 5.4%

Outcome Measures

1. Primary Outcome

Title	Percentage Reduction in C-reactive Protein (CRP)
Time Frame	14 weeks

Outcome Measure Data

Analysis Population Description

As hsCRP was measured at both 6 and 14 weeks, linear mixed models conditioning on baseline hsCRP and adjusting for treatment stratum were constructed with the dependent variable being change in lnCRP. Any subject having either or both 6 week and 14 week measures was included.

Arm/Group Title	Placebo Pill	Metformin Pill	Insulin Glargine Plus Placebo Pill	Insulin Glargine Plus Metformin Pill
Arm/Group Description	Placebo pill	Metformin pill	Insulin glargine plus placebo pill	Insulin Glargine plus metformin pill
Measure Participants	120	124	124	119
Mean (95% Confidence Interval) [Percent CRP Reduction]	-19.0	-16.1	-2.9	-20.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Pill, Metformin Pill, Insulin Glargine Plus Placebo Pill, Insulin Glargine Plus Metformin Pill
	Comments	As hsCRP was measured at both 6 and 14 weeks, linear mixed models conditioning on baseline hsCRP and adjusting for treatment stratum were constructed with the dependent variable being change in lnCRP. The means at each time point were estimated from a repeated-measures model incorporating all 3 time points. The interventions were assessed by fitting terms corresponding to study drug and treatment arm assignment.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	Mixed Models Analysis
	Comments	Adjusted models included terms for baseline HbA1c and weight and change in weight at each time point.
Method of Estimation	Estimation Parameter	Percent Change in Log CRP
	Estimated Value	20
	Confidence Interval	(2-Sided) 95%; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 10
	Estimation Comments

Adverse Events

Time Frame	14 weeks
Adverse Event Reporting Description	Occurrence of marked hypoglycemia, weight gain, and other adverse events were collected at each of 6 visits.
Arm/Group Title	Placebo Pill		Metformin Pill		Insulin Glargine Plus Placebo Pill		Insulin Glargine Plus Metformin Pill
Arm/Group Description	Placebo pill		Metformin pill		Insulin glargine plus placebo pill		Insulin Glargine plus metformin pill
All Cause Mortality
	Placebo Pill		Metformin Pill		Insulin Glargine Plus Placebo Pill		Insulin Glargine Plus Metformin Pill
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo Pill		Metformin Pill		Insulin Glargine Plus Placebo Pill		Insulin Glargine Plus Metformin Pill
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/124 (2.4%)		8/126 (6.3%)		2/126 (1.6%)		0/124 (0%)
Cardiac disorders
Supraventricular Tachycardia Requiring Hospitalization	0/124 (0%)	0	1/126 (0.8%)	1	0/126 (0%)	0	0/124 (0%)	0
Chest Pain Hospitalization	0/124 (0%)	0	2/126 (1.6%)	2	1/126 (0.8%)	1	0/124 (0%)	0
Endocrine disorders
Hyperglycemia Requiring Hospitalization	1/124 (0.8%)	1	0/126 (0%)	0	0/126 (0%)	0	0/124 (0%)	0
Gastrointestinal disorders
Severe Diarrhea Requiring Hospitalization	0/124 (0%)	0	1/126 (0.8%)	1	0/126 (0%)	0	0/124 (0%)	0
Gastroenteritis Hospitalization	0/124 (0%)	0	2/126 (1.6%)	2	0/126 (0%)	0	0/124 (0%)	0
Infections and infestations
Cellulitis Hospitalization	1/124 (0.8%)		0/126 (0%)	0	0/126 (0%)	0	0/124 (0%)	0
Sepsis Hospitazation	1/124 (0.8%)	1	0/126 (0%)	0	0/126 (0%)	0	0/124 (0%)	0
Musculoskeletal and connective tissue disorders
Traumatic Injury/Fracture	0/124 (0%)	0	1/126 (0.8%)	1	0/126 (0%)	0	0/124 (0%)	0
Psychiatric disorders
Depression	0/124 (0%)	0	1/126 (0.8%)	1	0/126 (0%)	0	0/124 (0%)	0
Renal and urinary disorders
Nephrolithiasis Requiring Hospitalization	0/124 (0%)	0	0/126 (0%)	0	1/126 (0.8%)	1	0/124 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo Pill		Metformin Pill		Insulin Glargine Plus Placebo Pill		Insulin Glargine Plus Metformin Pill
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/124 (9.7%)		18/126 (14.3%)		21/126 (16.7%)		17/124 (13.7%)
Endocrine disorders
Severe Hypoglycemia	1/124 (0.8%)	1	3/126 (2.4%)	3	3/126 (2.4%)	3	6/124 (4.8%)	6
Hyperglycemia: Confirmed Fasting Glucose >= 250 mg/dl	10/124 (8.1%)	10	1/126 (0.8%)	1	4/126 (3.2%)	4	1/124 (0.8%)	1
Hyperglycemia: Any Self-Monitor Blood Glucose >= 400 mg/dl	3/124 (2.4%)	3	0/126 (0%)	0	3/126 (2.4%)	3	1/124 (0.8%)	1
Weight Gain >= 5% of Baseline	3/124 (2.4%)	3	4/126 (3.2%)	4	14/126 (11.1%)	14	8/124 (6.5%)	8
Gastrointestinal disorders
Gastrointestinal Adverse Event (e.g. diarrhea not requiring hospitalization)	3/124 (2.4%)	3	13/126 (10.3%)	13	4/126 (3.2%)	4	8/124 (6.5%)	8

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT 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.