Safety and Efficacy Study to Compare Vildagliptin to Pioglitazone as Adding on Metformin in Type 2 Diabetes

• Sponsor: Pusan National University Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT01882907
• Collaborator: (none)
• Enrollment: 287
• Locations: 15
• Arms: 2
• Duration (Months): 39
• Patients Per Site: 19.1
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

The purpose of this study is to compare the effect of 16 weeks treatment with vildagliptin to pioglitazone as add-on the therapy to metformin in patients with type 2 diabetes inadequately controlled with metformin monotherapy.

Condition or Disease	Intervention/Treatment	Phase
Type 2 Diabetes	Drug: vildagliptin; Drug: Pioglitazone	Phase 4

Detailed Description

Type 2 diabetes mellitus (T2DM) is a chronic progressive disease characterized by hyperglycemia that result from pancreatic islet dysfunction. Presently available oral antihypoglycemic drug improves glycemic control over the short term, none has been shown to stop the progressive decline in beta cell function which contributes to the deterioration of glycemic control over time.

Pathophysiology of T2DM is known as tissue resistance for insulin and progressive beta cell failure. Which one attributes first is unclear, but non-obese T2DM patients often show normal fasting plasma glucose (FPG) but postprandial plasma glucose (PPG) level is high and reduced or lacking normal compensatory insulin secretion. In Korea, more than 80% of T2DM are non-obese type (BMI >= 27 ) and it was observed that basal insulin level and compensatory insulin secretion reaction were reduced in normal healthy population. Based on that, metformin is an established first line treatment for type 2 diabetes, acting primarily to enhance hepatic and peripheral insulin sensitivity. However, it has become increasingly apparent that many patients require a combination of agents to attain optimal glycemic control.

Better understanding of incretin effect on the pathophysiology of T2DM has recently led to development of new oral hypoglycemic agents. Vildagliptin is a potent and highly selective dipeptidyl peptidase (DPP)-IV inhibitor that improves islet function by increasing pancreatic alpha and beta cell responsiveness to glucose. Studies in patients with T2DM have shown that vildagliptin significantly reduced HbA1c and FPG level from baseline and did not induce weight gain and the incidence of hypoglycemia was low. In addition, studies in rodents support an effort of vildagliptin on beta cell remodeling.

The thiazolidinediones are effective in reducing HbA1C in obese T2DM patients and it is known that only thiazolidinedione can delay the beta cell failure . But recently, thiazolidinediones were found to be associated with a decrease in bone mineral density and to raise the risk of myocardial infarct and cardiovascular related mortality. Thus, there is a need for new classes of blood glucose lowering drug which has the potential to delay or prevent the progression of T2DM.

Study Design

• Study Type: Interventional
• Actual Enrollment: 287 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-label, Randomized, Active-controlled Study to Compare the Effect of 16 Weeks Treatment With Vildagliptin to Pioglitazone as add-on Therapy to Metformin in Type 2 Diabetic Patients Inadequately Controlled With Metformin Monotherapy
• Study Start Date: Dec 1, 2009
• Actual Primary Completion Date: Mar 1, 2013
• Actual Study Completion Date: Mar 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: vildagliptin vildagliptin add-on the therapy to metformin in patients with type 2 diabetes inadequately controlled with metformin monotherapy	Drug: vildagliptin; vildagliptin 50mg bid for 16 weeks; Other Names: Galvus
Active Comparator: pioglitazone Pioglitazone add-on the therapy to metformin in patients with type 2 diabetes inadequately controlled with metformin monotherapy	Drug: Pioglitazone; Pioglitazone 15mg bid for 16 weeks; Other Names: Actos

Outcome Measures

Primary Outcome Measures

1. Non-inferiority of HbA1C Change From Baseline in Vildagliptin + Metformin Group Compared With Pioglitazone + Metformin Group [16 weeks]

Secondary Outcome Measures

1. the Mean Changes of FPG and PPG From Baseline Between Vildagliptin + Metformin and Pioglitazone + Metformin Groups [16 weeks , visit 5]

   After 16 weeks, to assess the effect of vildagliptin compared with the effect of pioglitazone on Fasting Plasma Glucose (FPG) After 16 weeks, to assess the effect of vildagliptin compared with the effect of pioglitazone on Postprandial Glucose (PPG)

2. the Mean Changes of Lipid Profiles From Baseline Between Vildagliptin + Metformin and Pioglitazone + Metformin Groups [16 weeks, visit 5]

   The Mean Changes of Lipid Profiles(Triglyceride, Total cholesterol, LDL, HDL, Non-HDL cholesterol) From Baseline Between Vildagliptin + Metformin and Pioglitazone + Metformin Groups after 16weeks

3. the Mean Changes of Body Weight From Baseline Between Vildagliptin + Metformin and Pioglitazone + Metformin Groups [16 weeks, visit 5]

4. the Mean Changes of Insulin, C-peptide, HOMA-IR, HOMA-beta From Baseline Between Vildagliptin + Metformin and Pioglitazone + Metformin Groups [16 weeks, visit 5]

Other Outcome Measures

1. the Numbers of Participants With Adverse Events Between Vildagliptin + Metformin and Pioglitazone + Metformin Groups [16 weeks, visit 3,4,5]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Age in the range of 18 to 80 years

2. HbA1c 7 to 11%

3. FPG < 270 mg/dL (15 mmol/L);

4. Agreement to maintain prior diet & exercise

5. Written informed consent to participate in the study

Exclusion criteria:

1. Type 1 diabetes or Any kind of secondary diabetes

2. Pregnant or lactating women

3. Acute infections which may affect blood glucose control within 4 weeks prior to visit

5. Significant diabetes complications e.g., symptomatic autonomic neuropathy or gastroparesis

6. Previous history of severe cardiovascular disease such as

7. Torsades de Pointes, sustained and clinically relevant ventricular tachycardia, or ventricular fibrillation

8. Percutaneous coronary intervention within the past 3 months

9. Any of the following within the past 6 months

10. Myocardial infarction (MI) (if the visit 1 ECG reveals patterns consistent with an MI and the date of the event cannot be determined, then the patient can enter the study at the discretion of the investigator and the sponsor)

11. Coronary artery bypass surgery

12. Unstable angina

13. Stroke

14. Congestive heart failure (NYHA class I to IV)

15. Liver disease such as cirrhosis or chronic active hepatitis

16. Known sensitivity to pioglitazone, rosiglitazone, or similar drugs

17. Chronic insulin treatment (> 4 weeks of treatment in the absence of an intercurrent illness) within the past 6 months

18. Chronic oral or parenteral corticosteroid treatment (> 7 consecutive days of treatment) within 8 weeks prior to visit 1

19. Any of the following laboratory abnormalities

20. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) greater than 2.5 times the upper limit of the normal range at visit 1

21. Direct bilirubin greater than 1.3 times the upper limit of the normal range at visit 1

22. Serum creatinine levels > 2.5 mg/dL (220 μmol/L) at visit 1

23. Clinically significant thyroid-stimulating hormone (TSH) outside normal range at visit 1

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Busan Saint Mary's Medical Center	Busan		Korea, Republic of
2	Dong-AUniversity Medical Center	Busan		Korea, Republic of
3	Inje University Baik Hospital	Busan		Korea, Republic of
4	Kosin University Hospital	Busan		Korea, Republic of
5	Pusan National University Hospital	Busan		Korea, Republic of
6	Changwon Fatima Hospital	Changwon		Korea, Republic of
7	Daegu Catholic University Medical Center	Daegu		Korea, Republic of
8	Keimyung University Dongsan Medical Center	Daegu		Korea, Republic of
9	Kyungbuk National Universtiy Hospital	Daegu		Korea, Republic of
10	Chonnam National University Hospital	Gwangju		Korea, Republic of
11	Chosun University Hospital	Gwangju		Korea, Republic of
12	Chonbuk National University Hospital	Jeonju		Korea, Republic of
13	Gyeongsang National University Hospital	Jinju		Korea, Republic of
14	Masan Samsung Medical Center	Masan		Korea, Republic of
15	Ulsan University Hospital	Ulsan		Korea, Republic of

Sponsors and Collaborators

• Pusan National University Hospital

Investigators

• Principal Investigator: In Ju Kim, MD, Pusan National University Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Pusan National University Hospital
• ClinicalTrials.gov Identifier: NCT01882907
• Other Study ID Numbers: CLAF237AKR05T
• First Posted: Jun 21, 2013
• Last Update Posted: Mar 21, 2019
• Last Verified: Dec 1, 2018

• Keywords provided by Pusan National University Hospital: vildagliptin; metformin
• Additional relevant MeSH terms: Diabetes Mellitus, Type 2; Pioglitazone; Vildagliptin

Study Results

Participant Flow

Pre-assignment Detail	Total number of patients who were in screening is 287. However, 59 patients were excluded. 49 Patients didn't meet inclusion/exclusion criteria. 10 Patients didn't take investigational product. As a result, 228 patients took investigational product.

Arm/Group Title	Vildagliptin	Pioglitazone
Arm/Group Description	vildagliptin add-on the therapy to metformin in patients with type 2 diabetes inadequately controlled with metformin monotherapy vildagliptin: vildagliptin 50mg bid for 16 weeks	Pioglitazone add-on the therapy to metformin in patients with type 2 diabetes inadequately controlled with metformin monotherapy Pioglitazone: Pioglitazone 15mg bid for 16 weeks
Period Title: Overall Study
STARTED	117	111
COMPLETED	103	83
NOT COMPLETED	14	28

Baseline Characteristics

Arm/Group Title	Vildagliptin	Pioglitazone	Total
Arm/Group Description	vildagliptin add-on the therapy to metformin in patients with type 2 diabetes inadequately controlled with metformin monotherapy vildagliptin: vildagliptin 50mg bid for 16 weeks	Pioglitazone add-on the therapy to metformin in patients with type 2 diabetes inadequately controlled with metformin monotherapy Pioglitazone: Pioglitazone 15mg bid for 16 weeks	Total of all reporting groups
Overall Participants	117	111	228
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55.2 (9.8)	53.9 (9.1)	54.5 (9.5)
Sex: Female, Male (Count of Participants)
Female	67 57.3%	63 56.8%	130 57%
Male	50 42.7%	48 43.2%	98 43%
Body Mass Index (Kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Kg/m^2]	24.9 (3.2)	25.0 (3.3)	24.9 (3.3)
Duration of diaebetes (months) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [months]	68.3 (62.0)	60.2 (58.6)	64.3 (60.4)

Outcome Measures

1. Primary Outcome

Title	Non-inferiority of HbA1C Change From Baseline in Vildagliptin + Metformin Group Compared With Pioglitazone + Metformin Group
Time Frame	16 weeks

Outcome Measure Data

Analysis Population Description

This number is analyzed subjects population(Vildagliptin group n=115, Pioglitazone group n=108). It is excluded the patients who are screening failure and not available to efficacy assessment.

Arm/Group Title	Vildagliptin	Pioglitazone
Arm/Group Description	vildagliptin add-on the therapy to metformin in patients with type 2 diabetes inadequately controlled with metformin monotherapy vildagliptin: vildagliptin 50mg bid for 16 weeks	Pioglitazone add-on the therapy to metformin in patients with type 2 diabetes inadequately controlled with metformin monotherapy Pioglitazone: Pioglitazone 15mg bid for 16 weeks
Measure Participants	115	108
Mean (Standard Deviation) [% (change of HbA1c)]	-0.94 (0.79)	-0.60 (1.12)

2. Secondary Outcome

Title	the Mean Changes of FPG and PPG From Baseline Between Vildagliptin + Metformin and Pioglitazone + Metformin Groups
Description	After 16 weeks, to assess the effect of vildagliptin compared with the effect of pioglitazone on Fasting Plasma Glucose (FPG) After 16 weeks, to assess the effect of vildagliptin compared with the effect of pioglitazone on Postprandial Glucose (PPG)
Time Frame	16 weeks , visit 5

Outcome Measure Data

Analysis Population Description

This number is analyzed subjects population(Vildagliptin group n=115, Pioglitazone group n=108). It is excluded the patients who are screening failure and not available to efficacy assessment.

Arm/Group Title	Vildagliptin	Pioglitazone
Arm/Group Description	vildagliptin add-on the therapy to metformin in patients with type 2 diabetes inadequately controlled with metformin monotherapy vildagliptin: vildagliptin 50mg bid for 16 weeks The mean changes in FPG from baseline to week 16 were -20.4 mg/dL The mean changes in PPG levels from baseline to week 16 were -60.2 mg/dL	Pioglitazone add-on the therapy to metformin in patients with type 2 diabetes inadequately controlled with metformin monotherapy Pioglitazone: Pioglitazone 15mg bid for 16 weeks The mean changes in FPG from baseline to week 16 were -15.0 mg/dL The mean changes in PPG levels from baseline to week 16 were -38.2 mg/dL
Measure Participants	115	108
FBG levels difference	-20.41 (34.81)	-15.04 (38.15)
PPG levels difference	-60.23 (75.48)	-38.19 (83.79)

3. Secondary Outcome

Title	the Mean Changes of Lipid Profiles From Baseline Between Vildagliptin + Metformin and Pioglitazone + Metformin Groups
Description	The Mean Changes of Lipid Profiles(Triglyceride, Total cholesterol, LDL, HDL, Non-HDL cholesterol) From Baseline Between Vildagliptin + Metformin and Pioglitazone + Metformin Groups after 16weeks
Time Frame	16 weeks, visit 5

Outcome Measure Data

Analysis Population Description

This number is analyzed subjects population(Vildagliptin group n=115, Pioglitazone group n=108). It is excluded the patients who are screening failure and not available to efficacy assessment.

Arm/Group Title	Vildagliptin	Pioglitazone
Arm/Group Description	vildagliptin add-on the therapy to metformin in patients with type 2 diabetes inadequately controlled with metformin monotherapy vildagliptin: vildagliptin 50mg bid for 16 weeks	Pioglitazone add-on the therapy to metformin in patients with type 2 diabetes inadequately controlled with metformin monotherapy Pioglitazone: Pioglitazone 15mg bid for 16 weeks
Measure Participants	115	108
Triglyceride	-9.22 (55.98)	-4.79 (67.83)
Total cholesterol	-6.45 (25.10)	9.60 (33.83)
LDL	-6.03 (21.20)	5.38 (30.37)
HDL	-0.34 (8.57)	3.69 (10.33)
Non-HDL cholesterol	-8.39 (24.67)	5.79 (32.72)

4. Secondary Outcome

Title	the Mean Changes of Body Weight From Baseline Between Vildagliptin + Metformin and Pioglitazone + Metformin Groups
Time Frame	16 weeks, visit 5

Outcome Measure Data

Analysis Population Description

This number is analyzed subjects population(Vildagliptin group n=115, Pioglitazone group n=108). It is excluded the patients who are screening failure and not available to efficacy assessment.

Arm/Group Title	Vildagliptin	Pioglitazone
Arm/Group Description	vildagliptin add-on the therapy to metformin in patients with type 2 diabetes inadequately controlled with metformin monotherapy vildagliptin: vildagliptin 50mg bid for 16 weeks	Pioglitazone add-on the therapy to metformin in patients with type 2 diabetes inadequately controlled with metformin monotherapy Pioglitazone: Pioglitazone 15mg bid for 16 weeks
Measure Participants	115	108
Mean (Standard Deviation) [kg]	-0.07 (1.53)	0.69 (2.07)

5. Secondary Outcome

Title	the Mean Changes of Insulin, C-peptide, HOMA-IR, HOMA-beta From Baseline Between Vildagliptin + Metformin and Pioglitazone + Metformin Groups
Time Frame	16 weeks, visit 5

Outcome Measure Data

Analysis Population Description

This number is analyzed subjects population(Vildagliptin group n=115, Pioglitazone group n=108). It is excluded the patients who are screening failure and not available to efficacy assessment.

Arm/Group Title	Vildagliptin	Pioglitazone
Arm/Group Description	vildagliptin add-on the therapy to metformin in patients with type 2 diabetes inadequately controlled with metformin monotherapy vildagliptin: vildagliptin 50mg bid for 16 weeks	Pioglitazone add-on the therapy to metformin in patients with type 2 diabetes inadequately controlled with metformin monotherapy Pioglitazone: Pioglitazone 15mg bid for 16 weeks
Measure Participants	115	108
Insulin difference	0.36 (6.95)	-8.21 (70.06)
C-peptide difference	0.07 (0.84)	-0.24 (1.14)
HOMA-IR difference	-0.06 (2.92)	-3.33 (25.16)
HOMA-beta difference	9.77 (28.10)	-24.26 (294.88)

6. Other Pre-specified Outcome

Title	the Numbers of Participants With Adverse Events Between Vildagliptin + Metformin and Pioglitazone + Metformin Groups
Time Frame	16 weeks, visit 3,4,5

Outcome Measure Data

Analysis Population Description

This number is subject population who were exposure the drug(Vildagliptin group n=117, Pioglitazone group n=111). It is excluded the patients who are screening failure.

Arm/Group Title	Vildagliptin	Pioglitazone
Arm/Group Description	vildagliptin add-on the therapy to metformin in patients with type 2 diabetes inadequately controlled with metformin monotherapy vildagliptin: vildagliptin 50mg bid for 16 weeks	Pioglitazone add-on the therapy to metformin in patients with type 2 diabetes inadequately controlled with metformin monotherapy Pioglitazone: Pioglitazone 15mg bid for 16 weeks
Measure Participants	117	111
Number of incidence	27 23.1%	25 22.5%
Number of adverse events	48 41%	37 33.3%

Adverse Events

Arm/Group Title	Vildagliptin		Pioglitazone
Arm/Group Description	vildagliptin add-on the therapy to metformin in patients with type 2 diabetes inadequately controlled with metformin monotherapy vildagliptin: vildagliptin 50mg bid for 16 weeks		Pioglitazone add-on the therapy to metformin in patients with type 2 diabetes inadequately controlled with metformin monotherapy Pioglitazone: Pioglitazone 15mg bid for 16 weeks
All Cause Mortality
	Vildagliptin		Pioglitazone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Vildagliptin		Pioglitazone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/117 (3.4%)		2/111 (1.8%)
Cardiac disorders
Myocardial infarction	1/117 (0.9%)	1	0/111 (0%)	0
Immune system disorders
Urinary tract infection	1/117 (0.9%)	1	0/111 (0%)	0
Infections and infestations
Upper respiration infection	1/117 (0.9%)	1	1/111 (0.9%)	1
Musculoskeletal and connective tissue disorders
Injury of ligament	1/117 (0.9%)	1	0/111 (0%)	0
Nervous system disorders
Dizziness	0/117 (0%)	0	2/111 (1.8%)	2
Other (Not Including Serious) Adverse Events
	Vildagliptin		Pioglitazone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	16/117 (13.7%)		11/111 (9.9%)
Gastrointestinal disorders
Nausea	3/117 (2.6%)		2/111 (1.8%)
Diarrhea	3/117 (2.6%)		1/111 (0.9%)
Dyspepsia	3/117 (2.6%)		0/111 (0%)
Infections and infestations
Common cold	3/117 (2.6%)		4/111 (3.6%)
Upper respiration infection	4/117 (3.4%)		0/111 (0%)
Nervous system disorders
Dizziness	0/117 (0%)		4/111 (3.6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.