Colesevelam as Add-on to Pioglitazone Therapy for Type 2 Diabetes Mellitus

• Sponsor: Daiichi Sankyo, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00789750
• Collaborator: (none)
• Enrollment: 562
• Locations: 141
• Arms: 2
• Duration (Months): 39
• Patients Per Site: 4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The current study investigates colesevelam as add-on therapy to pioglitazone to improve glycemic control in subjects with type 2 diabetes mellitus not adequately controlled with pioglitazone monotherapy or pioglitazone in combination with either metformin or a sulfonylurea. The study will evaluate if colesevelam add-on to pioglitazone therapy for type 2 diabetes mellitus will be safe, well tolerated, and efficacious.

Condition or Disease	Intervention/Treatment	Phase
Type 2 Diabetes Mellitus	Drug: Colesevelam; Drug: Placebo; Drug: Pioglitazone	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 562 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Placebo Controlled, Parallel Group Study of the Efficacy and Safety of WELCHOL as Add-on to Pioglitazone Therapy for Type 2 Diabetes Mellitus (T2DM)
• Study Start Date: Apr 1, 2009
• Actual Primary Completion Date: Jul 1, 2012
• Actual Study Completion Date: Jul 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Colesevelam Participants receive six colesevelam tablets (3.8 grams/day) in addition to pioglitazone-based therapy (30 mg or 45 mg)	Drug: Colesevelam; Colesevelam 625 mg tablets; Other Names: Welchol ; Drug: Pioglitazone; 30 mg or 45 mg pioglitazone therapy; Other Names: Actos
Placebo Comparator: Placebo Participants receive six placebo tablets in addition to pioglitazone-based therapy (30 mg or 45 mg)	Drug: Placebo; Placebo tablets appearing to be colesevelam; Other Names: No drug ; Drug: Pioglitazone; 30 mg or 45 mg pioglitazone therapy; Other Names: Actos

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Hemoglobin A1c (HbA1c) at Week 24 [Baseline, Week 24]

Secondary Outcome Measures

1. Change From Baseline in HbA1c at Week 4 [Baseline, Week 4]

2. Change From Baseline in HbA1c at Week 8 [Baseline, Week 8]

3. Change From Baseline in HbA1c at Week 16 [Baseline, Week 16]

4. Number of Participants Achieving an HbA1c Goal of <7.0% [Week 24]

5. Change From Baseline in Fasting Plasma Glucose (FPG) [Baseline, Week 24]

   In this study a reduction in FPG of at least 30 mg/dL is considered glycemic response.

6. Number of Participants With a Decrease of >= 0.7 Percent in HbA1c [Week 24]

7. Number of Participants With a Decrease of >= 0.5 Percent in HbA1c [Week 24]

8. Number of Participants With a Reduction in FPG of >= 30 mg/dL [Week 24]

9. Percent Change From Baseline in Total Cholesterol (TC) [Baseline, Week 24]

   TC is measured in milligrams per deciliter (mg/dL)

10. Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) [Baseline, Week 24]

    LDL-C is measured in mg/dL

11. Percent Change From Baseline in High-density Lipoprotein Cholesterol (HDL-C) [Baseline, Week 24]

    HDL-C is measured in mg/dL

12. Percent Change From Baseline in Non-HDL-C [Baseline, Week 24]

    Non-HDL-C is measured in mg/dL

13. Percent Change From Baseline in Triglycerides (TG) [Baseline, Week 24]

    TG are measured in mg/dL

14. Percent Change From Baseline in Apolipoprotein A-1 (Apo A-I) [Baseline, Week 24]

    Apo A-1 is measured in mg/dL

15. Percent Change From Baseline in Apolipoprotein B (Apo B) [Baseline, Week 24]

    Apo B is measured in mg/dL

16. Change From Baseline in Fasting Insulin Levels [Baseline, Week 24]

17. Change From Baseline in Fasting C-peptide [Baseline, Week 24]

18. Change From Baseline in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) [Baseline, Week 24]

    HOMA-IR is a calculation of fasting insulin and fasting glucose that shows the level of insulin resistance. Lower numbers are better.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Diagnosis of Type 2 diabetes mellitus

• Inadequate glycemic control on a stable dose (at least 2 months prior to screening) of pioglitazone at 30 or 45 mg/day, with or without one or two other oral antidiabetic medications [metformin or a sulfonylurea, or dipeptidyl peptidase (DPP-IV) inhibitor]

• Hemoglobin A1c (HbA1c) >= 7.5% and =< 9.5% at screening

• Fasting plasma glucose =<240 mg/dL at randomization (Week 0/Day 1).

• Male or female >= 18 years of age.

• Women of childbearing potential must be using an adequate method of contraception as detailed per-protocol

• Fasting C-peptide level >0.5 ng/mL at screening

• Clinically stable in regards to medical conditions other than type 2 diabetes

• Concomitant medications are at stable doses for at least 30 days prior to enrollment, and are not anticipated to need adjustment during the study period

Exclusion Criteria:

• History of Type 1 diabetes and/or history of ketoacidosis

• History of bowel obstruction

• History of hypertriglyceridemia-induced pancreatitis

• Fasting serum triglyceride concentration >500 mg/dL

• History of dysphagia, swallowing disorders, gastroparesis, other gastrointestinal motility disorders, major gastrointestinal surgery

• History of insulin use >= 2 weeks duration during the previous 3 months or a total of

2 months insulin therapy at any time prior to screening

• Treatment with bile acid sequestrants, including colesevelam within 3 months prior to screening

• Female subject who is pregnant or breastfeeding

• History of unstable angina, myocardial infarction, cerebrovascular accident, transient ischemic attack, or any revascularization within 6 months prior to screening

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Birmingham	Alabama	United States	35205
2		Birmingham	Alabama	United States	35216
3		Birmingham	Alabama	United States	35294
4		Montgomery	Alabama	United States	36106
5		Montgomery	Alabama	United States	36117
6		Green Valley	Arizona	United States	85614
7		Mesa	Arizona	United States	85210
8		Phoenix	Arizona	United States	85050
9		Tempe	Arizona	United States	85282
10		Tempe	Arizona	United States	85284
11		Searcy	Arkansas	United States	72143
12		Buena Park	California	United States	90620
13		Burbank	California	United States	91505
14		Chino	California	United States	91710
15		Garden Grove	California	United States	92844
16		Huntington Park	California	United States	90255
17		La Mirada	California	United States	90638
18		Lincoln	California	United States	95648
19		Lomita	California	United States	90717
20		Los Gatos	California	United States	95032
21		Modesto	California	United States	95355
22		San Diego	California	United States	92161
23		Santa Ana	California	United States	92701
24		Tustin	California	United States	92780
25		Walnut Creek	California	United States	94598
26		Coral Gables	Florida	United States	33134
27		DeLand	Florida	United States	32720
28		Delray Beach	Florida	United States	33484
29		Gulf Breeze	Florida	United States	32561
30		Hialeah	Florida	United States	33012
31		Jacksonville	Florida	United States	32223
32		Kissimmee	Florida	United States	34741
33		Miami	Florida	United States	33135
34		Miami	Florida	United States	33156
35		Miami	Florida	United States	33169
36		Miami	Florida	United States	33175
37		Miami	Florida	United States	33183
38		New Port Richey	Florida	United States	34652
39		Ocala	Florida	United States	34471
40		Ormond Beach	Florida	United States	32174
41		Pembroke Pines	Florida	United States	33026
42		Pembroke Pines	Florida	United States	33027
43		Pinellas Park	Florida	United States	33781
44		Sanford	Florida	United States	32771
45		Tampa	Florida	United States	33607
46		Vero Beach	Florida	United States	32960
47		Wellington	Florida	United States	33449
48		Winter Haven	Florida	United States	33880
49		Winter Park	Florida	United States	32789
50		Winter Park	Florida	United States	32792
51		Columbus	Georgia	United States	31904
52		Decatur	Georgia	United States	30035
53		East Point	Georgia	United States	30344
54		Marietta	Georgia	United States	30066
55		Roswell	Georgia	United States	30076
56		Stockbridge	Georgia	United States	30281
57		Tucker	Georgia	United States	30084
58		Waycross	Georgia	United States	31501
59		Nampa	Idaho	United States	83686
60		Arlington Heights	Illinois	United States	60004
61		Chicago	Illinois	United States	60607
62		Bloomington	Indiana	United States	47403
63		Evansville	Indiana	United States	47714
64		LaPorte	Indiana	United States	46350
65		South Bend	Indiana	United States	46614
66		Crestview Hills	Kentucky	United States	41017
67		Paducah	Kentucky	United States	42003
68		Lafayette	Louisiana	United States	70503
69		Prince Frederick	Maryland	United States	20678
70		Silver Spring	Maryland	United States	20910
71		New Bedford	Massachusetts	United States	02740
72		Southfield	Michigan	United States	48034
73		Brooklyn Center	Minnesota	United States	55430
74		Jackson	Mississippi	United States	39216
75		Port Gibson	Mississippi	United States	39150
76		Kansas City	Missouri	United States	64111
77		Saint Louis	Missouri	United States	63141
78		Billings	Montana	United States	59101
79		Las Vegas	Nevada	United States	89123
80		Belvidere	New Jersey	United States	07823
81		Berlin	New Jersey	United States	08009
82		Clifton	New Jersey	United States	07013
83		Lumberton	New Jersey	United States	08048
84		Mine Hill	New Jersey	United States	07803
85		New Windsor	New York	United States	12553
86		North Massapequa	New York	United States	11758
87		Tonawanda	New York	United States	14150
88		West Seneca	New York	United States	14224
89		Lexington	North Carolina	United States	27293
90		Statesville	North Carolina	United States	28625
91		Cincinnati	Ohio	United States	45219
92		Cincinnati	Ohio	United States	45227
93		Cincinnati	Ohio	United States	45245
94		Cleveland	Ohio	United States	44122
95		Columbus	Ohio	United States	43213
96		Cuyahoga Falls	Ohio	United States	44223
97		Marion	Ohio	United States	43302
98		Shaker Heights	Ohio	United States	44120
99		Stow	Ohio	United States	44224
100		Oklahoma City	Oklahoma	United States	73103
101		Oklahoma City	Oklahoma	United States	73132
102		Oklahoma City	Oklahoma	United States	73159
103		Portland	Oregon	United States	97220
104		Harrisburg	Pennsylvania	United States	17112
105		Jersey Shore	Pennsylvania	United States	17740
106		Philadelphia	Pennsylvania	United States	19140
107		Philadelphia	Pennsylvania	United States	19153
108		Upper Saint Clair	Pennsylvania	United States	15241
109		Charleston	South Carolina	United States	29412
110		Charleston	South Carolina	United States	29414
111		Columbia	South Carolina	United States	29201
112		Greer	South Carolina	United States	29651
113		Germantown	Tennessee	United States	38138
114		Jackson	Tennessee	United States	38305
115		Murfreesboro	Tennessee	United States	37130
116		New Tazewell	Tennessee	United States	37825
117		Arlington	Texas	United States	76012
118		Dallas	Texas	United States	75230
119		Dallas	Texas	United States	75231
120		Dallas	Texas	United States	75235
121		Fort Worth	Texas	United States	76117
122		Grand Prairie	Texas	United States	75052
123		Houston	Texas	United States	77008
124		Houston	Texas	United States	77074
125		Houston	Texas	United States	77081
126		Houston	Texas	United States	77083
127		San Antonio	Texas	United States	78209
128		San Antonio	Texas	United States	78229
129		Sugar Land	Texas	United States	77478
130		Sugar Land	Texas	United States	77479
131		Tomball	Texas	United States	77375
132		Salt Lake City	Utah	United States	84102
133		Salt Lake City	Utah	United States	84107
134		Alexandria	Virginia	United States	22304
135		Danville	Virginia	United States	24541
136		Manassas	Virginia	United States	20110
137		Richmond	Virginia	United States	23225
138		Salem	Virginia	United States	24153
139		Suffolk	Virginia	United States	23435
140		Lakewood	Washington	United States	98499
141		Kenosha	Wisconsin	United States	53142

Sponsors and Collaborators

• Daiichi Sankyo, Inc.

Investigators

• Study Director: Global Clinical Leader, Daiichi Sankyo, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Daiichi Sankyo, Inc.
• ClinicalTrials.gov Identifier: NCT00789750
• Other Study ID Numbers: WEL-A-U306
• First Posted: Nov 13, 2008
• Last Update Posted: Jun 26, 2017
• Last Verified: Jun 1, 2017

• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Pioglitazone; Colesevelam Hydrochloride

Study Results

Participant Flow

Recruitment Details	The safety set includes all randomized participants who took at least one dose of study medication and have at least one post-baseline safety measurement. The intent-to-treat set includes all randomized subjects who took at least one dose of study medication, and had a baseline and at least one post-baseline HbA1c or FPG measurement.
Pre-assignment Detail	There was a lead-in period that occurred after participant enrollment, but before randomization.1538 were screened, and a total of 562 participants were randomized.

Arm/Group Title	Colesevelam	Placebo
Arm/Group Description	Colesevelam tablets with pioglitazone therapy	Placebo tablets with pioglitazone therapy
Period Title: Overall Study
STARTED	280	282
Dropped During run-in Period	6	5
Safety Set	274	277
Intent to Treat Set	271	276
COMPLETED	221	222
NOT COMPLETED	59	60

Baseline Characteristics

Arm/Group Title	Colesevelam	Placebo	Total
Arm/Group Description	Colesevelam tablets with pioglitazone therapy	Placebo tablets with pioglitazone therapy	Total of all reporting groups
Overall Participants	280	282	562
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	220 78.6%	222 78.7%	442 78.6%
>=65 years	60 21.4%	60 21.3%	120 21.4%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	56.3 (10.22)	55.6 (10.61)	56.0 (10.41)
Sex: Female, Male (Count of Participants)
Female	136 48.6%	106 37.6%	242 43.1%
Male	144 51.4%	176 62.4%	320 56.9%
Race/Ethnicity, Customized (Count of Participants)
Caucasian	179 63.9%	172 61%	351 62.5%
Black	59 21.1%	56 19.9%	115 20.5%
Asian	23 8.2%	30 10.6%	53 9.4%
American Indian or Alaskan Native	16 5.7%	21 7.4%	37 6.6%
Native Hawaiian or Pacific Islander	0 0%	1 0.4%	1 0.2%
Other	3 1.1%	2 0.7%	5 0.9%
Region of Enrollment (participants) [Number]
United States	280 100%	282 100%	562 100%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Hemoglobin A1c (HbA1c) at Week 24
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

Intent-to-treat, last observation carried forward

Arm/Group Title	Colesevelam	Placebo
Arm/Group Description	Colesevelam tablets with pioglitazone therapy	Placebo tablets with pioglitazone therapy
Measure Participants	271	276
Least Squares Mean (Standard Error) [percent]	-0.34 (0.083)	-0.02 (0.083)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Colesevelam, Placebo
	Comments	Treatment difference = Colesevelam - Placebo
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.32
	Confidence Interval	(2-Sided) 95%; -0.49 to -0.16
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.084
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in HbA1c at Week 4
Time Frame	Baseline, Week 4

Outcome Measure Data

Analysis Population Description

Intent to treat set, with baseline and post-baseline measures at the given time point

Arm/Group Title	Colesevelam	Placebo
Arm/Group Description	Colesevelam tablets with pioglitazone therapy	Placebo tablets with pioglitazone therapy
Measure Participants	264	266
Least Squares Mean (Standard Error) [percent]	-0.28 (0.037)	-0.11 (0.037)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Colesevelam, Placebo
	Comments	Treatment difference = Colesevelam - Placebo
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.17
	Confidence Interval	(2-Sided) 95%; -0.24 to -0.10
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.037
	Estimation Comments

3. Secondary Outcome

Title	Change From Baseline in HbA1c at Week 8
Time Frame	Baseline, Week 8

Outcome Measure Data

Analysis Population Description

Intent to treat set, with baseline and post-baseline measures at the given time point

Arm/Group Title	Colesevelam	Placebo
Arm/Group Description	Colesevelam tablets with pioglitazone therapy	Placebo tablets with pioglitazone therapy
Measure Participants	256	256
Least Squares Mean (Standard Error) [percent]	-0.35 (0.055)	-0.14 (0.056)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Colesevelam, Placebo
	Comments	Treatment difference = Colesevelam - Placebo
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.21
	Confidence Interval	(2-Sided) 95%; -0.32 to -0.10
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.056
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline in HbA1c at Week 16
Time Frame	Baseline, Week 16

Outcome Measure Data

Analysis Population Description

Intent to treat set, with baseline and post-baseline measures at the given time point

Arm/Group Title	Colesevelam	Placebo
Arm/Group Description	Colesevelam tablets with pioglitazone therapy	Placebo tablets with pioglitazone therapy
Measure Participants	232	232
Least Squares Mean (Standard Error) [percent]	-0.50 (0.078)	-0.15 (0.078)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Colesevelam, Placebo
	Comments	Treatment difference = Colesevelam - Placebo
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.36
	Confidence Interval	(2-Sided) 95%; -0.51 to -0.20
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.077
	Estimation Comments

5. Secondary Outcome

Title	Number of Participants Achieving an HbA1c Goal of <7.0%
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

Intent-to-treat set, with last observation carried forward

Arm/Group Title	Colesevelam	Placebo
Arm/Group Description	Colesevelam tablets with pioglitazone therapy	Placebo tablets with pioglitazone therapy
Measure Participants	271	276
Count of Participants [Participants]	56 20%	35 12.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Colesevelam, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.012
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

6. Secondary Outcome

Title	Change From Baseline in Fasting Plasma Glucose (FPG)
Description	In this study a reduction in FPG of at least 30 mg/dL is considered glycemic response.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

Participants in the intent-to-treat set with values at both baseline and Week 24 with last observation carried forward

Arm/Group Title	Colesevelam	Placebo
Arm/Group Description	Colesevelam tablets with pioglitazone therapy	Placebo tablets with pioglitazone therapy
Measure Participants	268	270
Least Squares Mean (Standard Error) [mg/dL]	-4.8 (3.66)	9.9 (3.66)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Colesevelam, Placebo
	Comments	Treatment difference = Colesevelam - Placebo
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-14.7
	Confidence Interval	(2-Sided) 95%; -21.93 to -7.49
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.68
	Estimation Comments

7. Secondary Outcome

Title	Number of Participants With a Decrease of >= 0.7 Percent in HbA1c
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

Intent-to-treat set, with last count carried forward

Arm/Group Title	Colesevelam	Placebo
Arm/Group Description	Colesevelam tablets with pioglitazone therapy	Placebo tablets with pioglitazone therapy
Measure Participants	271	276
Count of Participants [Participants]	108 38.6%	70 24.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Colesevelam, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0003
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

8. Secondary Outcome

Title	Number of Participants With a Decrease of >= 0.5 Percent in HbA1c
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

Intent-to-treat set, with last count carried forward

Arm/Group Title	Colesevelam	Placebo
Arm/Group Description	Colesevelam tablets with pioglitazone therapy	Placebo tablets with pioglitazone therapy
Measure Participants	271	276
Count of Participants [Participants]	147 52.5%	106 37.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Colesevelam, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

9. Secondary Outcome

Title	Number of Participants With a Reduction in FPG of >= 30 mg/dL
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

Intent-to-treat set, with last count carried forward

Arm/Group Title	Colesevelam	Placebo
Arm/Group Description	Colesevelam tablets with pioglitazone therapy	Placebo tablets with pioglitazone therapy
Measure Participants	271	276
Count of Participants [Participants]	60 21.4%	47 16.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Colesevelam, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.132
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

10. Secondary Outcome

Title	Percent Change From Baseline in Total Cholesterol (TC)
Description	TC is measured in milligrams per deciliter (mg/dL)
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

Intent-to-treat set, with values at both baseline and Week 24 with last observation carried forward

Arm/Group Title	Colesevelam	Placebo
Arm/Group Description	Colesevelam tablets with pioglitazone therapy	Placebo tablets with pioglitazone therapy
Measure Participants	263	263
Least Squares Mean (Standard Error) [percentage of change]	-3.4 (1.33)	3.1 (1.32)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Colesevelam, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments

11. Secondary Outcome

Title	Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C)
Description	LDL-C is measured in mg/dL
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

Intent-to-treat set, with values at both baseline and Week 24 with last count carried forward

Arm/Group Title	Colesevelam	Placebo
Arm/Group Description	Colesevelam tablets with pioglitazone therapy	Placebo tablets with pioglitazone therapy
Measure Participants	262	263
Least Squares Mean (Standard Error) [percentage of change]	-9.1 (2.14)	7.3 (2.12)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Colesevelam, Placebo
	Comments	Treatment difference = Colesevelam - Placebo
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-16.4
	Confidence Interval	(2-Sided) 95%; -20.62 to -12.18
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.15
	Estimation Comments

12. Secondary Outcome

Title	Percent Change From Baseline in High-density Lipoprotein Cholesterol (HDL-C)
Description	HDL-C is measured in mg/dL
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

Intent-to-treat set, with values at both baseline and Week 24 with last observation carried forward

Arm/Group Title	Colesevelam	Placebo
Arm/Group Description	Colesevelam tablets with pioglitazone therapy	Placebo tablets with pioglitazone therapy
Measure Participants	263	263
Least Squares Mean (Standard Error) [percentage of change]	2.9 (1.30)	1.1 (1.30)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Colesevelam, Placebo
	Comments	Treatment difference = Colesevelam - Placebo
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1652
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.8
	Confidence Interval	(2-Sided) 95%; -0.75 to 4.39
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.31
	Estimation Comments

13. Secondary Outcome

Title	Percent Change From Baseline in Non-HDL-C
Description	Non-HDL-C is measured in mg/dL
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

Intent-to-treat set, with values at both baseline and Week 24 with last observation carried forward

Arm/Group Title	Colesevelam	Placebo
Arm/Group Description	Colesevelam tablets with pioglitazone therapy	Placebo tablets with pioglitazone therapy
Measure Participants	263	263
Least Squares Mean (Standard Error) [percentage of change]	-5.2 (1.85)	4.6 (1.84)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Colesevelam, Placebo
	Comments	Treatment difference = Colesevelam - Placebo
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-9.8
	Confidence Interval	(2-Sided) 95%; -13.44 to -6.16
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.85
	Estimation Comments

14. Secondary Outcome

Title	Percent Change From Baseline in Triglycerides (TG)
Description	TG are measured in mg/dL
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

Intent-to-treat set, with values at both baseline and Week 24 with last observation carried forward

Arm/Group Title	Colesevelam	Placebo
Arm/Group Description	Colesevelam tablets with pioglitazone therapy	Placebo tablets with pioglitazone therapy
Measure Participants	263	263
Median (Inter-Quartile Range) [percentage of change]	14.1	2.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Colesevelam, Placebo
	Comments	Treatment difference = Colesevelam - Placebo
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0004
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	11.3
	Confidence Interval	(2-Sided) 95%; 5.3 to 17.5
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 67.01
	Estimation Comments	The treatment difference and its 95% confidence interval are estimated using the Hodges-Lehmann estimator and Moses method. The parameter dispersion Type is actually IQR of the Median Difference.

15. Secondary Outcome

Title	Percent Change From Baseline in Apolipoprotein A-1 (Apo A-I)
Description	Apo A-1 is measured in mg/dL
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

Intent-to-treat, with values at both baseline and Week 24 with last observation carried forward

Arm/Group Title	Colesevelam	Placebo
Arm/Group Description	Colesevelam tablets with pioglitazone therapy	Placebo tablets with pioglitazone therapy
Measure Participants	263	262
Least Squares Mean (Standard Error) [percentage of change]	3.2 (0.92)	-0.2 (0.92)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Colesevelam, Placebo
	Comments	Treatment difference = Colesevelam - Placebo
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0003
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3.4
	Confidence Interval	(2-Sided) 95%; 1.58 to 5.23
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.93
	Estimation Comments

16. Secondary Outcome

Title	Percent Change From Baseline in Apolipoprotein B (Apo B)
Description	Apo B is measured in mg/dL
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

Intent-to-treat set, with values at both baseline and Week 24 with last observation carried forward

Arm/Group Title	Colesevelam	Placebo
Arm/Group Description	Colesevelam tablets with pioglitazone therapy	Placebo tablets with pioglitazone therapy
Measure Participants	263	262
Least Squares Mean (Standard Error) [percentage of change]	-5.2 (1.51)	3.6 (1.51)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Colesevelam, Placebo
	Comments	Treatment difference = Colesevelam - Placebo
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-8.8
	Confidence Interval	(2-Sided) 95%; -11.75 to -5.78
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.52
	Estimation Comments

17. Secondary Outcome

Title	Change From Baseline in Fasting Insulin Levels
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

Intent-to-treat set, with values at both baseline and Week 24 with last observation carried forward

Arm/Group Title	Colesevelam	Placebo
Arm/Group Description	Colesevelam tablets with pioglitazone therapy	Placebo tablets with pioglitazone therapy
Measure Participants	246	248
Least Squares Mean (Standard Error) [µIU/mL]	0.2 (1.76)	0.8 (1.76)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Colesevelam, Placebo
	Comments	Treatment difference = Colesevelam - Placebo
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7286
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.6
	Confidence Interval	(2-Sided) 95%; -4.1 to 2.9
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.77
	Estimation Comments

18. Secondary Outcome

Title	Change From Baseline in Fasting C-peptide
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

Intent-to-treat set, with values at both baseline and Week 24 with last observation carried forward

Arm/Group Title	Colesevelam	Placebo
Arm/Group Description	Colesevelam tablets with pioglitazone therapy	Placebo tablets with pioglitazone therapy
Measure Participants	253	255
Least Squares Mean (Standard Error) [ng/mL]	0.1 (0.10)	0.3 (0.10)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Colesevelam, Placebo
	Comments	Treatment difference = Colesevelam - Placebo
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0653
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 95%; -0.4 to 0.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.11
	Estimation Comments

19. Secondary Outcome

Title	Change From Baseline in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)
Description	HOMA-IR is a calculation of fasting insulin and fasting glucose that shows the level of insulin resistance. Lower numbers are better.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

Intent-to-treat set, with values at both baseline and Week 24 with last observation carried forward

Arm/Group Title	Colesevelam	Placebo
Arm/Group Description	Colesevelam tablets with pioglitazone therapy	Placebo tablets with pioglitazone therapy
Measure Participants	227	227
Least Squares Mean (Standard Error) [calculation]	0.2 (0.71)	0.3 (0.72)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Colesevelam, Placebo
	Comments	Treatment difference = Colesevelam - Placebo
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8862
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -1.5 to 1.3
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.73
	Estimation Comments

Adverse Events

Time Frame	Adverse events that first occurred or worsened in severity after initiation of treatment with the investigational product and up to the end of study assessment and follow-up period, within 3 years, 3 months
Adverse Event Reporting Description	Four potential cardiac events were referred to the Clinical Event Committee (CEC) for adjudication: 1 event was adjudicated as stroke and was considered unrelated to study treatment, while 3 were adjudicated as noncardiac chest pain. No serious adverse events in either treatment group were considered drug-related.
Arm/Group Title	Colesevelam		Placebo
Arm/Group Description	Colesevelam tablets with pioglitazone therapy		Placebo tablets with pioglitazone therapy
All Cause Mortality
	Colesevelam		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/274 (0%)		0/277 (0%)
Serious Adverse Events
	Colesevelam		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/274 (4%)		4/277 (1.4%)
Blood and lymphatic system disorders
Leukopenia	0/274 (0%)		1/277 (0.4%)
Gastrointestinal disorders
Inguinal hernia	1/274 (0.4%)		0/277 (0%)
General disorders
Non-cardiac chest pain	2/274 (0.7%)		1/277 (0.4%)
Infections and infestations
Diabetic foot infection	1/274 (0.4%)		0/277 (0%)
Gastroenteritis	0/274 (0%)		1/277 (0.4%)
Osteomyelitis	1/274 (0.4%)		0/277 (0%)
Pneumonia	0/274 (0%)		1/277 (0.4%)
Urinary tract infection	1/274 (0.4%)		0/277 (0%)
Metabolism and nutrition disorders
Dehydration	0/274 (0%)		2/277 (0.7%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lung squamous cell carcinoma stage unspecified	1/274 (0.4%)		0/277 (0%)
Prostate cancer	1/274 (0.4%)		0/277 (0%)
Nervous system disorders
Cerebrovascular accident	1/274 (0.4%)		0/277 (0%)
Presyncope	1/274 (0.4%)		0/277 (0%)
Syncope	1/274 (0.4%)		0/277 (0%)
Psychiatric disorders
Bipolar disorder	1/274 (0.4%)		0/277 (0%)
Vascular disorders
Hypertension	1/274 (0.4%)		0/277 (0%)
Other (Not Including Serious) Adverse Events
	Colesevelam		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/274 (4%)		17/277 (6.1%)
Metabolism and nutrition disorders
Hypoglycaemia	11/274 (4%)		17/277 (6.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

PI agrees to wait until after coordinated multicenter publication or one year after the trial is over, whichever occurs first. After such time, Study Site will submit any publication to DSI for CCI review and comment at least forty-five (45) days prior to submission. Site agrees to delay publication for an additional sixty (60) days for legal (e.g., patent) concerns. Nothing shall be taken as giving DSI any right of editorial control over any publication prepared by Study Site.