Effects of Colesevelam on How the Body Responds to Insulin in Patients With Type 2 Diabetes

• Sponsor: Daiichi Sankyo, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00147745
• Collaborator: (none)
• Enrollment: 36
• Location: 1
• Arms: 3
• Duration (Months): 31
• Patients Per Site Per Month: 1.2

Study Details

Study Description

Brief Summary

This study is designed to assess the potential mechanism of action by which WelChol® (colesevelam) may improve blood glucose control in patients with type 2 diabetes

Condition or Disease	Intervention/Treatment	Phase
Type 2 Diabetes	Drug: Colesevelam; Drug: Colesevelam matching placebo; Drug: Insulin glargine (Lantus)	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 36 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Care Provider)
• Primary Purpose: Treatment
• Official Title: Effects of Colesevelam on Insulin Sensitivity in Type 2 Diabetes Mellitus
• Study Start Date: Jun 1, 2005
• Actual Primary Completion Date: Jan 1, 2008
• Actual Study Completion Date: Jan 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 colesevelam 3.8g administered daily for 12 weeks	Drug: Colesevelam; Colesevelam 3.8g for 12 weeks
Placebo Comparator: 2 Colesevelam matching placebo for 12 weeks	Drug: Colesevelam matching placebo; Colesevelam matching placebo for 12 weeks
Active Comparator: 3 open-label Insulin Glargine for 12 weeks	Drug: Insulin glargine (Lantus); Insulin glargine for 12 weeks

Outcome Measures

Primary Outcome Measures

1. Difference in Endogenous (Hepatic) Glucose Output During a High-dose Insulin Infusion From Baseline to After 12 Weeks of Treatment. [Baseline to 12 weeks]

   The parameter measured is the endogenous (hepatic) glucose output during a high-dose insulin infusion. A decrease after treatment with colesevelam is indicative of greater sensitivity of the liver to insulin.

2. Difference in Endogenous (Hepatic) Glucose Output During a Low-dose Insulin Infusion From Baseline to Week 12. [Baseline to 12 weeks]

   The parameter measured is the endogenous (hepatic) glucose output during a low-dose insulin infusion. A decrease is indicative of greater senstitivity of the liver to insulin.

3. Acute Effect of a Single Dose of Colesevelam on Oral Glucose Absorption From Baseline to First Dose [Baseline (Day -4) to first dose (Day 1)]

   Change in area under the curve for glucose (AUCg) after a glucose tolerance test. A decrease in AUCg is indicative of a drug effect.

Secondary Outcome Measures

1. The Acute Effect of Colesevelam (Multiple Doses) on Oral Glucose Absorption From Baseline to 12 Weeks [Baseline to 12 weeks]

   The parameter measured is the change in area under the curve for glucose(AUCg) after an oral glucose tolerance test. A decrease in AUCg indicative of drug effect on glucose absorption.

2. Change in Hemoglobin A1C Due to Effect of Colesevelam From Baseline to 12 Weeks [Baseline to 12 weeks]

   The parameter measured is the percent of hemoglobin A that is glycosylated. A decrease in this parameter is indicative of improved glucose control.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients between the ages of 18 - 75, inclusive

• Diagnosed with type 2 diabetes

• Hemoglobin A1c value greater than or equal to 8.0%

• Antidiabetic treatments may include sulfonylurea agents (non-sulfonylurea agents must be withdrawn)

• Overweight, obese (body mass index 25-45 kg/m2)

Exclusion Criteria:

• Change of dose of lipid or blood pressure lowering therapy within past three months

• Previous treatment with colesevelam for hyperlipidemia

• Serum triglyceride greater than 500 mg/dL

• Serum low density lipoprotein-cholesterol less than 60 mg/dL

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	San Diego VMC	San Diego	California	United States	92161

Sponsors and Collaborators

• Daiichi Sankyo, Inc.

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Daiichi Sankyo, Inc.
• ClinicalTrials.gov Identifier: NCT00147745
• Other Study ID Numbers: WEL-201
• First Posted: Sep 7, 2005
• Last Update Posted: Apr 2, 2014
• Last Verified: Mar 1, 2014

• Keywords provided by Daiichi Sankyo, Inc.: Mechanism of action insulin sensitivity
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Insulin Glargine; Colesevelam Hydrochloride

Study Results

Participant Flow

Recruitment Details	Subjects were recruited from 21 June 2005 to 22 January 2008 at 3 clinical research sites in the United States of America.
Pre-assignment Detail	Subjects were taken off any non-sulfonylurea oral anti-diabetic agents for a period of time appropriate to the drug. Qualified subjects were randomized to colesevelam hydrochloride, placebo, or open-label insulin glargine for 12 weeks. Difficulties enrolling into the insulin group caused the size of this group to decrease from 15 to 6 subjects.

Arm/Group Title	Colesevelam 3.8g	Colesevelam Matching Placebo	Open-label Insulin Glargine
Arm/Group Description	colesevelam 3.8g administered daily for 12 weeks	Colesevelam matching placebo for 12 weeks	open-label Insulin Glargine for 12 weeks
Period Title: Overall Study
STARTED	16	14	6
COMPLETED	15	14	6
NOT COMPLETED	1	0	0

Baseline Characteristics

Arm/Group Title	Colesevelam 3.8g	Colesevelam Matching Placebo	Open-label Insulin Glargine	Total
Arm/Group Description	colesevelam 3.8g administered daily for 12 weeks	Colesevelam matching placebo for 12 weeks	open-label Insulin Glargine for 12 weeks	Total of all reporting groups
Overall Participants	16	14	6	36
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	55.7	54.0	52.8	54.6
Sex: Female, Male (Count of Participants)
Female	4 25%	6 42.9%	1 16.7%	11 30.6%
Male	12 75%	8 57.1%	5 83.3%	25 69.4%
Race/Ethnicity, Customized (Number) [Number]
Hispanic	1 6.3%	2 14.3%	2 33.3%	5 13.9%
Black or African American	5 31.3%	3 21.4%	1 16.7%	9 25%
White	8 50%	9 64.3%	3 50%	20 55.6%
Unknown or Not Reported	2 12.5%	0 0%	0 0%	2 5.6%
Region of Enrollment (participants) [Number]
United States	16 100%	14 100%	6 100%	36 100%
Body Mass (kg/m2) [Mean (Full Range) ]
Mean (Full Range) [kg/m2]	33.7	33.7	35.2	34.0
Fasting Plasma Glucose (mg/dL) [Mean (Full Range) ]
Mean (Full Range) [mg/dL]	162.6	207.9	199.0	186.3
HbA1c (percent) [Mean (Full Range) ]
Mean (Full Range) [percent]	8.2	8.5	9.3	8.5
Height (cm) [Mean (Full Range) ]
Mean (Full Range) [cm]	171.7	168.6	170.8	170.4
Weight (kg) [Mean (Full Range) ]
Mean (Full Range) [kg]	98.6	95.8	103.4	98.3

Outcome Measures

1. Primary Outcome

Title	Difference in Endogenous (Hepatic) Glucose Output During a High-dose Insulin Infusion From Baseline to After 12 Weeks of Treatment.
Description	The parameter measured is the endogenous (hepatic) glucose output during a high-dose insulin infusion. A decrease after treatment with colesevelam is indicative of greater sensitivity of the liver to insulin.
Time Frame	Baseline to 12 weeks

Outcome Measure Data

Analysis Population Description

The population analyzed was all randomized subjects who received medication and had a baseline and at least 1 post-randomization assessment of an efficacy variable. One placebo participant did not have a valid post-randomization insulin clamp study. Therefore, the number included in the placebo group for this analysis was 13.

Arm/Group Title	Colesevelam 3.8g	Colesevelam Matching Placebo	Open-label Insulin Glargine
Arm/Group Description	colesevelam 3.8g administered daily for 12 weeks	Colesevelam matching placebo for 12 weeks	open-label Insulin Glargine for 12 weeks
Measure Participants	15	13	6
Least Squares Mean (Standard Error) [mg/kg/min]	-0.06 (0.048)	-0.011 (0.051)	-0.01 (0.076)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Colesevelam 3.8g, Colesevelam Matching Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5499
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.04
	Confidence Interval	() 95%; -0.10 to 0.19
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.070
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Colesevelam 3.8g, Open-label Insulin Glargine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5723
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.05
	Confidence Interval	() 95%; -0.23 to 0.13
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.090
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Colesevelam Matching Placebo, Open-label Insulin Glargine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3138
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.09
	Confidence Interval	() 95%; -0.09 to 0.28
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.091
	Estimation Comments

2. Primary Outcome

Title	Difference in Endogenous (Hepatic) Glucose Output During a Low-dose Insulin Infusion From Baseline to Week 12.
Description	The parameter measured is the endogenous (hepatic) glucose output during a low-dose insulin infusion. A decrease is indicative of greater senstitivity of the liver to insulin.
Time Frame	Baseline to 12 weeks

Outcome Measure Data

Analysis Population Description

The population analyzed was all randomized subjects who received medication and had a baseline and at least 1 post-randomization assessment of an efficacy variable. One placebo participant did not have a valid post-randomization insulin clamp study. Therefore, the number included in the placebo group for this analysis was 13.

Arm/Group Title	Colesevelam 3.8g	Colesevelam Matching Placebo	Open-label Insulin Glargine
Arm/Group Description	colesevelam 3.8g administered daily for 12 weeks	Colesevelam matching placebo for 12 weeks	open-label Insulin Glargine for 12 weeks
Measure Participants	15	13	6
Least Squares Mean (Standard Error) [mg/kg/min]	-0.08 (0.044)	-0.16 (0.048)	-0.04 (0.070)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Colesevelam 3.8g, Colesevelam Matching Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2042
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.08
	Confidence Interval	() 95%; -0.05 to 0.22
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.065
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Colesevelam 3.8g, Open-label Insulin Glargine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6855
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.03
	Confidence Interval	() 95%; -0.20 to 0.14
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.083
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Colesevelam Matching Placebo, Open-label Insulin Glargine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1727
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.12
	Confidence Interval	() 95%; -0.05 to 0.29
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.085
	Estimation Comments

3. Secondary Outcome

Title	The Acute Effect of Colesevelam (Multiple Doses) on Oral Glucose Absorption From Baseline to 12 Weeks
Description	The parameter measured is the change in area under the curve for glucose(AUCg) after an oral glucose tolerance test. A decrease in AUCg indicative of drug effect on glucose absorption.
Time Frame	Baseline to 12 weeks

Outcome Measure Data

Analysis Population Description

One participant in the colesevelam 3.8g group discontinued. Therefore, 15 participants were included in this analysis.

Arm/Group Title	Colesevelam 3.8g	Colesevelam Matching Placebo	Open-label Insulin Glargine
Arm/Group Description	colesevelam 3.8g administered daily for 12 weeks	Colesevelam matching placebo for 12 weeks	open-label Insulin Glargine for 12 weeks
Measure Participants	15	14	6
Least Squares Mean (Standard Error) [mg*hr/dL]	-49.1 (36.75)	-4.7 (36.93)	-59.3 (57.27)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Colesevelam 3.8g, Colesevelam Matching Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4104
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-44.4
	Confidence Interval	() 95%; -152.8 to 64.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 53.17
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Colesevelam 3.8g, Open-label Insulin Glargine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8857
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	10.1
	Confidence Interval	() 95%; -132.6 to 152.9
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 69.98
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Colesevelam Matching Placebo, Open-label Insulin Glargine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4226
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-54.5
	Confidence Interval	() 95%; -191.3 to 82.3
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 67.08
	Estimation Comments

4. Secondary Outcome

Title	Change in Hemoglobin A1C Due to Effect of Colesevelam From Baseline to 12 Weeks
Description	The parameter measured is the percent of hemoglobin A that is glycosylated. A decrease in this parameter is indicative of improved glucose control.
Time Frame	Baseline to 12 weeks

Outcome Measure Data

Analysis Population Description

One participant in the colesevelam 3.8g group discontinued. Therefore, 15 participants were included in this analysis. The least squares mean is adjusted for baseline values. This corrects for differences in baseline values between treatment groups.

Arm/Group Title	Colesevelam 3.8g	Colesevelam Matching Placebo	Open-label Insulin Glargine
Arm/Group Description	colesevelam 3.8g administered daily for 12 weeks	Colesevelam matching placebo for 12 weeks	open-label Insulin Glargine for 12 weeks
Measure Participants	15	14	6
Least Squares Mean (Standard Error) [percent]	-0.29 (0.258)	0.16 (0.260)	-0.81 (0.426)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Colesevelam 3.8g, Colesevelam Matching Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2286
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.45
	Confidence Interval	() 95%; -1.20 to 0.30
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.366
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Colesevelam 3.8g, Open-label Insulin Glargine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3184
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.52
	Confidence Interval	() 95%; -0.53 to 1.57
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.515
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Colesevelam Matching Placebo, Open-label Insulin Glargine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0613
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.97
	Confidence Interval	() 95%; -1.99 to 0.05
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.500
	Estimation Comments

5. Primary Outcome

Title	Acute Effect of a Single Dose of Colesevelam on Oral Glucose Absorption From Baseline to First Dose
Description	Change in area under the curve for glucose (AUCg) after a glucose tolerance test. A decrease in AUCg is indicative of a drug effect.
Time Frame	Baseline (Day -4) to first dose (Day 1)

Outcome Measure Data

Analysis Population Description

The entire study population was included in this analysis

Arm/Group Title	Colesevelam 3.8g
Arm/Group Description	colesevelam 3.8g administered daily for 12 weeks
Measure Participants	36
Mean (Standard Deviation) [mg*hr/dL]	-38.4 (105.75)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Colesevelam 3.8g
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0362
	Comments
	Method	t-test, 2 sided
	Comments

Adverse Events

Time Frame	12 week treatment period plus 30 days after the last dose of study medication.
Arm/Group Title	Colesevelam 3.8g		Colesevelam Matching Placebo		Open-label Insulin Glargine
Arm/Group Description	colesevelam 3.8g administered daily for 12 weeks		Colesevelam matching placebo for 12 weeks		open-label Insulin Glargine for 12 weeks
All Cause Mortality
	Colesevelam 3.8g		Colesevelam Matching Placebo		Open-label Insulin Glargine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Colesevelam 3.8g		Colesevelam Matching Placebo		Open-label Insulin Glargine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/16 (0%)		0/14 (0%)		0/6 (0%)
Other (Not Including Serious) Adverse Events
	Colesevelam 3.8g		Colesevelam Matching Placebo		Open-label Insulin Glargine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/16 (87.5%)		10/14 (71.4%)		4/6 (66.7%)
Cardiac disorders
ventricular extrasystoles	0/16 (0%)	0	1/14 (7.1%)	0	0/6 (0%)	0
Gastrointestinal disorders
Abdominal Pain Upper	0/16 (0%)	0	1/14 (7.1%)	0	0/6 (0%)	0
Constipation	6/16 (37.5%)		1/14 (7.1%)		0/6 (0%)	0
Diarrhea NOS	1/16 (6.3%)		1/14 (7.1%)		0/6 (0%)	0
Flatulence	0/16 (0%)	0	1/14 (7.1%)	0	0/6 (0%)	0
Gastroesophageal Reflux disease	1/16 (6.3%)		0/14 (0%)	0	0/6 (0%)	0
Vomiting NOS	0/16 (0%)	0	1/14 (7.1%)	0	0/6 (0%)	0
General disorders
Infusion site pain	0/16 (0%)	0	2/14 (14.3%)	0	0/6 (0%)	0
Oedema	1/16 (6.3%)		1/14 (7.1%)		0/6 (0%)	0
Immune system disorders
Seasonal allergy	0/16 (0%)	0	0/14 (0%)	0	1/6 (16.7%)	0
Infections and infestations
Ear Infection NOS	1/16 (6.3%)		0/14 (0%)	0	0/6 (0%)	0
Nasopharyngitis	1/16 (6.3%)		2/14 (14.3%)		0/6 (0%)	0
Sinusitis	0/16 (0%)	0	0/14 (0%)	0	1/6 (16.7%)	0
Tooth Abcess	1/16 (6.3%)		0/14 (0%)	0	1/6 (16.7%)	0
Vaginosis Fungal NOS	0/16 (0%)	0	1/14 (7.1%)	0	0/6 (0%)	0
Viral Infection NOS	1/16 (6.3%)		0/14 (0%)	0	0/6 (0%)	0
Injury, poisoning and procedural complications
Heat exhaustion	1/16 (6.3%)		0/14 (0%)	0	0/6 (0%)	0
Investigations
Electrocardiogram QT prolonged	1/16 (6.3%)		0/14 (0%)	0	0/6 (0%)	0
Elecrtocariogram ST Segment Depression	1/16 (6.3%)		0/14 (0%)	0	0/6 (0%)	0
Electrocardiogram T Wave Abnormal	2/16 (12.5%)		0/14 (0%)	0	0/6 (0%)	0
Electrocardiogram T Wave Inversion	0/16 (0%)	0	2/14 (14.3%)	0	0/6 (0%)	0
Heart Rate Increased	1/16 (6.3%)		0/14 (0%)	0	0/6 (0%)	0
Musculoskeletal and connective tissue disorders
Back Pain	1/16 (6.3%)		0/14 (0%)	0	0/6 (0%)	0
Pain in Extremity	0/16 (0%)	0	1/14 (7.1%)	0	1/6 (16.7%)	0
Nervous system disorders
Headache	2/16 (12.5%)		5/14 (35.7%)		1/6 (16.7%)
Migraine NOS	0/16 (0%)	0	1/14 (7.1%)	0	0/6 (0%)	0
Reproductive system and breast disorders
Dysmenorrhea	0/16 (0%)	0	1/14 (7.1%)	0	0/6 (0%)	0
Erectile Dysfunction NOS	0/16 (0%)	0	0/14 (0%)	0	1/6 (16.7%)	0
Respiratory, thoracic and mediastinal disorders
Cough	1/16 (6.3%)		0/14 (0%)	0	0/6 (0%)	0
Pharyngolaryngeal Pain	1/16 (6.3%)		2/14 (14.3%)		1/6 (16.7%)
Sinus Pain	0/16 (0%)	0	0/14 (0%)	0	1/6 (16.7%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

If identified by Daiichi Sankyo, Inc. (DSI), any of DSI's confidential information as defined herein shall be deleted…Nothing in this publication section shall be taken as giving DSI any right of editorial control over any publication prepared by Study Site.