Effect of Different Interventions on Glycemic Control and β-cell Function in Newly Diagnosed Type 2 Diabetic Patients

• Sponsor: Sun Yat-sen University (Other)
• Overall Status: Completed
• CT.gov ID: NCT01147627
• Collaborator: Eli Lilly and Company (Industry), Amylin Pharmaceuticals, LLC. (Industry), Ministry of Health, China (Other)
• Enrollment: 416
• Locations: 25
• Arms: 3
• Duration (Months): 28
• Patients Per Site: 16.6
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

The purpose of this study is to investigate and evaluate the effects of different interventions (1. exenatide, 2. insulin, 3. thiazolidinedione) on glycemic control and β-cell function in newly diagnosed drug-naïve type 2 diabetic patients.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus, Type 2; Newly Diagnosed	Drug: exenatide injection; Drug: Mixed Protamine Zinc Recombinant Human Insulin Lispro 25R; Drug: Pioglitazone	N/A

Detailed Description

One of the fundamental defects in type 2 diabetes mellitus is declining β-cell function. Exenatide targets multiple metabolic disturbances in type 2 diabetes and exerts direct effects on β-cell, which indicates that it may not only contribute to the glucose control but also delay disease progression. There are trials demonstrated efficacy, safety and tolerability of exenatide. However, no study has compared the effects of exenatide with other hypoglycemic therapies with β cell protective function in newly diagnosed and drug-naïve type 2 diabetic patients. This current study is thus designed to evaluate the effects of exenatide, insulin and pioglitazone on glycemic control and β-cell function in newly diagnosed drug-naïve type 2 diabetic patients.

Study Design

• Study Type: Interventional
• Actual Enrollment: 416 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Comparison of Exenatide, Insulin or Pioglitazone on Glycaemic Control and β-cell Function in Drug-naïve Type 2 Diabetic Patients: A Multicentre Randomized Parallel-group Trial
• Study Start Date: Aug 1, 2010
• Actual Primary Completion Date: Aug 1, 2012
• Actual Study Completion Date: Dec 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Exenatide	Drug: exenatide injection; Patients in exenatide group will be treated with exenatide (Byetta®, Eli Lilly and Company) 5 µg BID for the first 4 weeks and then 10 µg BID thereafter.; Other Names: Byetta®(Eli Lilly and Company)
Active Comparator: Premixed insulin analog	Drug: Mixed Protamine Zinc Recombinant Human Insulin Lispro 25R; Patients in insulin group will be treated with premixed insulin analog (Humalog Mix 25, Eli Lilly and Company). The initial insulin doses are 0.4 IU/kg per day(50% before breakfast and 50% before dinner). Insulin doses are titrated following a forced schedule according to blood glucose before breakfast and dinner.; Other Names: Humalog Mix 25®（Eli Lilly and Company)
Active Comparator: pioglitazone	Drug: Pioglitazone; Patients in thiazolidinedione group will be treated with Pioglitazone 30mg daily as single dose. The dose will be increased to 45mg daily after 4 weeks.

Outcome Measures

Primary Outcome Measures

1. the Comparison Between Treatment Groups of the Changes From Baseline in HbA1c at 48 Weeks [48 weeks]

Secondary Outcome Measures

1. Percentage of Patients Achieving HbA1c <7% and ≤ 6.5% and Effect of Different Interventions on Fasting and Postprandial Plasma Glucose Concentration, Blood Pressure, Lipid Profiles [48 weeks]

2. β-cell Function (Acute Insulin Response During IVGTT; HOMA-B, Disposition Index and Proinsulin/Insulin Ratio) [48 weeks]

3. Safety and Tolerability in Different Groups [48 weeks]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 30 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• newly-diagnosed type 2 diabetic patients, drug naïve

• age 30~70 years

• HbA1c 7.0~10.0%

• BMI 20~35 kg/m2, stable body weight (≤10% variation) for at least 3 months prior to screening

• female patients of reproductive age should practice a reliable method of birth control throughout the study

Exclusion Criteria:

• acute or severe chronic diabetic complications

• congestive heart failure (NYHA grade Ⅲ~Ⅳ)

• severe gastrointestinal disease

• severe osteoporosis or history of pathological fracture,or use of bisphosphonates preparation

• other severe intercurrent illness

• serum aminotransferase (ALT and AST) level higher than 2 times of the upper normal limits and/or serum creatinie≥133µmol/L (1.5mg/dL)

• tested positive for glutamic acid decarboxylase antibody

• use of weight loss drugs, corticosteroids, drugs known to affect gastrointestinal motility, transplantation medications, or any investigational drug

• history of pancreatitis

• serum triglyceride ≥ 5.0 mmol/L

• pregnancy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	China-Japan Friendship Hospital	Beijing	Beijing	China	100029
2	Peking University People's Hospital	Beijing	Beijing	China	100044
3	Beijing Hospital	Beijing	Beijing	China	100730
4	Chinese PLA General Hospital	Beijing	Beijing	China	100853
5	Peking University First Hospital	Beijing	Beijing	China
6	The Military General Hospital of Beijing PLA	Beijing	Beijing	China
7	The Second Affiliated Hospital of Sun Yat-sen University	Guangzhou	Guangdong	China	510000
8	The Third Affiliated Hospital of Sun Yat-sen University	Guangzhou	Guangdong	China	510630
9	Qingyuan People's hospital	Qingyuan	Guangdong	China	511500
10	The first Affiliated Hospital of Shantou University Medical College	Shantou	Guangdong	China	515041
11	Shenzhen Second People's Hospital	Shenzhen	Guangdong	China	518035
12	Affiliated hospital of Guangdong medical college	Zhanjiang	Guangdong	China	524001
13	The first affiliated hospital of Guangxi Medical College	Nanning	Guangxi	China	530000
14	The Affiliated Hospital of Guiyang Medical College	Guiyang	Guizhou	China
15	The 2nd Affiliated Hospital of Harbin Medical University	Harbin	Heilongjiang	China
16	Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology	Wuhan	Hubei	China
17	Second Xiangya Hospital of Central-south University	Changsha	Hunan	China	410011
18	The Affiliated Hospital of Inner Mangolia Medical College	Hohhot	Inner Mongolia	China
19	Nanjing Drum Tower Hospital of Nanjing University Medical School	Nanjing	Jiangsu	China
20	The First Affiliated Hospital of Nanjing Medical University	Nanjing	Jiangsu	China
21	Zhongda Hospital of Southeast University	Nanjing	Jiangsu	China
22	China Medical University	Shenyang	Liaoning	China	110001
23	Xijing Hospital of The Fourth Military Medical University	Xian	Shaanxi	China
24	The First Affiliated Hospital of Kunming Medical College	Kunming	Yunnan	China
25	The First Affiliated Hospital of Chongqing Medical University	Chongqing		China

Sponsors and Collaborators

• Sun Yat-sen University
• Eli Lilly and Company
• Amylin Pharmaceuticals, LLC.
• Ministry of Health, China

Investigators

• Study Director: Jianping Weng, Doctor, Third Affiliated Hospital, Sun Yat-Sen University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Jianping Weng, professor, vice president, the third affiliated hospital of Sun Yat-sen University, Sun Yat-sen University
• ClinicalTrials.gov Identifier: NCT01147627
• Other Study ID Numbers: IIT-201007-WJP
• First Posted: Jun 22, 2010
• Last Update Posted: Aug 21, 2013
• Last Verified: Jun 1, 2013

• Keywords provided by Jianping Weng, professor, vice president, the third affiliated hospital of Sun Yat-sen University, Sun Yat-sen University: diabetes mellitus, type 2; newly diagnosed; exenatide; premixed insulin analog; thiazolidinedione; β-cell function; glycemic control
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Insulin; Pioglitazone; Exenatide; Insulin Lispro; Insulin, Globin Zinc; Protamines

Study Results

Participant Flow

Arm/Group Title	Exenatide	Premixed Insulin Analog	Pioglitazone
Arm/Group Description	5 µg was injected twice-daily subcutaneously increasing to 10 µg twice-daily after 4 weeks. Those who experienced hypoglycaemia frequently or could not tolerate adverse events were instructed to reduce the dose to 5 µg twice-daily.	Premixed insulin was injected twice-daily commencing with 0.4 IU/kg daily, with 50% given 15 minutes before breakfast and dinner respectively	Pioglitazone was commenced at a dose of 30 mg daily, increasing to 45 mg daily after 4 weeks.
Period Title: Overall Study
STARTED	142	138	136
COMPLETED	110	114	118
NOT COMPLETED	32	24	18

Baseline Characteristics

Arm/Group Title	Exenatide	Premixed Insulin Analog	Thiazolidinedione	Total
Arm/Group Description	Total of all reporting groups
Overall Participants	142	138	136	416
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	132 93%	128 92.8%	129 94.9%	389 93.5%
>=65 years	10 7%	10 7.2%	7 5.1%	27 6.5%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	49.89 (9.64)	51.39 (9.65)	49.66 (8.86)	50.31 (9.40)
Sex: Female, Male (Count of Participants)
Female	44 31%	53 38.4%	53 39%	150 36.1%
Male	98 69%	85 61.6%	83 61%	266 63.9%
Region of Enrollment (participants) [Number]
China	142 100%	138 100%	136 100%	416 100%

Outcome Measures

1. Primary Outcome

Title	the Comparison Between Treatment Groups of the Changes From Baseline in HbA1c at 48 Weeks
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Exenatide	Premixed Insulin Analog	Thiazolidinedione
Arm/Group Description
Measure Participants	110	114	118
Mean (Standard Deviation) [percentage of HbA1c]	-1.8 (1.29)	-1.74 (1.16)	-1.47 (1.30)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Exenatide, Premixed Insulin Analog, Thiazolidinedione
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	108 patients in each group was needed to provide 90% power to detect non-inferiority of exenatide, shown by a mean difference of 0.4% in HbA1c change from baseline.
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	ANCOVA
	Comments

2. Secondary Outcome

Title	Percentage of Patients Achieving HbA1c <7% and ≤ 6.5% and Effect of Different Interventions on Fasting and Postprandial Plasma Glucose Concentration, Blood Pressure, Lipid Profiles
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Secondary Outcome

Title	β-cell Function (Acute Insulin Response During IVGTT; HOMA-B, Disposition Index and Proinsulin/Insulin Ratio)
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Safety and Tolerability in Different Groups
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Arm/Group Title	Exenatide		Premixed Insulin Analog		Thiazolidinedione
Arm/Group Description
All Cause Mortality
	Exenatide		Premixed Insulin Analog		Thiazolidinedione
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Exenatide		Premixed Insulin Analog		Thiazolidinedione
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/142 (3.5%)		1/138 (0.7%)		7/136 (5.1%)
Gastrointestinal disorders
Acute pancreatitis	1/142 (0.7%)		0/138 (0%)		0/136 (0%)
Musculoskeletal and connective tissue disorders
Cervical spondylosis	0/142 (0%)		0/138 (0%)		1/136 (0.7%)
Thigh myofascitis	1/142 (0.7%)		0/138 (0%)		0/136 (0%)
Linguinal herniation	0/142 (0%)		0/138 (0%)		1/136 (0.7%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cholangiocellular carcinoma	1/142 (0.7%)		0/138 (0%)		0/136 (0%)
Nervous system disorders
Facial neuritis	0/142 (0%)		0/138 (0%)		1/136 (0.7%)
Renal and urinary disorders
Acute nephritis	0/142 (0%)		0/138 (0%)		1/136 (0.7%)
Proteinuria	1/142 (0.7%)		0/138 (0%)		0/136 (0%)
Respiratory, thoracic and mediastinal disorders
Pneumonia	0/142 (0%)		0/138 (0%)		1/136 (0.7%)
Skin and subcutaneous tissue disorders
Furuncle and secondary skin infection	0/142 (0%)		0/138 (0%)		1/136 (0.7%)
Vascular disorders
Cerebral infarction	1/142 (0.7%)		0/138 (0%)		0/136 (0%)
Cerebral infarction	0/142 (0%)		1/138 (0.7%)		0/136 (0%)
Cerebral infarction	0/142 (0%)		0/138 (0%)		1/136 (0.7%)
Other (Not Including Serious) Adverse Events
	Exenatide		Premixed Insulin Analog		Thiazolidinedione
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	69/142 (48.6%)		42/138 (30.4%)		43/136 (31.6%)
Cardiac disorders
palpitation	4/142 (2.8%)		2/138 (1.4%)		2/136 (1.5%)
chest tightness	2/142 (1.4%)		0/138 (0%)		3/136 (2.2%)
Eye disorders
blurred vision	2/142 (1.4%)		1/138 (0.7%)		3/136 (2.2%)
Gastrointestinal disorders
Nausea	37/142 (26.1%)		1/138 (0.7%)		1/136 (0.7%)
Vomitting	15/142 (10.6%)		1/138 (0.7%)		1/136 (0.7%)
abdominal pain	5/142 (3.5%)		2/138 (1.4%)		5/136 (3.7%)
diarrhea	6/142 (4.2%)		1/138 (0.7%)		4/136 (2.9%)
abdominal distention	8/142 (5.6%)		0/138 (0%)		1/136 (0.7%)
appetite loss	8/142 (5.6%)		0/138 (0%)		0/136 (0%)
constipation	6/142 (4.2%)		0/138 (0%)		1/136 (0.7%)
General disorders
edema	0/142 (0%)		0/138 (0%)		12/136 (8.8%)
fatigue	3/142 (2.1%)		3/138 (2.2%)		4/136 (2.9%)
Weight gain	0/142 (0%)		1/138 (0.7%)		0/136 (0%)
Immune system disorders
allergy	0/142 (0%)		1/138 (0.7%)		0/136 (0%)
Musculoskeletal and connective tissue disorders
arthralgia	0/142 (0%)		1/138 (0.7%)		4/136 (2.9%)
skelalgia	3/142 (2.1%)		1/138 (0.7%)		1/136 (0.7%)
Nervous system disorders
dizziness	18/142 (12.7%)		7/138 (5.1%)		4/136 (2.9%)
numbness	4/142 (2.8%)		2/138 (1.4%)		5/136 (3.7%)
headache	3/142 (2.1%)		2/138 (1.4%)		2/136 (1.5%)
toothache	3/142 (2.1%)		2/138 (1.4%)		0/136 (0%)
Respiratory, thoracic and mediastinal disorders
upper respiratory tract infection	16/142 (11.3%)		13/138 (9.4%)		11/136 (8.1%)
Skin and subcutaneous tissue disorders
injection site reaction	4/142 (2.8%)		6/138 (4.3%)		0/136 (0%)
rash	1/142 (0.7%)		2/138 (1.4%)		2/136 (1.5%)

Limitations/Caveats

The open-label design, which could have introduced bias by affecting patients' expectations and adherence to therapy.

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.