Comparison of Repaglinide and Gliclazide in Chinese Subjects With Type 2 Diabetes Never Received Oral Antidiabetic Drug Treatment

• Sponsor: Novo Nordisk A/S (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01022762
• Collaborator: (none)
• Enrollment: 440
• Location: 1
• Arms: 2
• Duration (Months): 12
• Patients Per Site Per Month: 36.7

Study Details

Study Description

Brief Summary

This trial is conducted in Asia. The aim of this clinical trial is to investigate the blood glucose lowering effect and the safety profile of repaglinide given alone compared to gliclazide given alone in Chinese subjects with type 2 diabetes who never have been treated with oral anti-diabetic drugs (OADs). This study also investigates the augment effect of repaglinide on the phases of insulin secretion as a subgroup study.

Condition or Disease	Intervention/Treatment	Phase
Diabetes; Diabetes Mellitus, Type 2	Drug: repaglinide; Drug: gliclazide	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 440 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A 16-week, Multicentre, Randomised, Open-label, Parallel Group Study to Investigate the Efficacy and Safety Profiles of Repaglinide Monotherapy Compared to Gliclazide Monotherapy in Chinese Antidiabetic-naïve Subjects With Type 2 Diabetes
• Study Start Date: Nov 1, 2009
• Actual Primary Completion Date: Nov 1, 2010
• Actual Study Completion Date: Nov 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: repaglinide 1 mg repaglinide twice daily (weeks 0-4), titrated (individually adjusted) to maintenance dose (weeks 4-16). Maximum dose is 4 mg three times daily	Drug: repaglinide; Individually adjusted dose for 16 weeks
Active Comparator: gliclazide 80 mg gliclazide once daily (weeks 0-4), titrated (individually adjusted) to maintenance dose (weeks 4-16). Maximum dose is 160 mg twice daily	Drug: gliclazide; Individually adjusted dose for 16 weeks

Outcome Measures

Primary Outcome Measures

1. Change in Glycosylated Haemoglobin (HbA1c) [Week 0, week 16]

Secondary Outcome Measures

1. Change in Fasting Plasma Glucose [Week 0, week 16]

2. Change in 2-hour Postprandial Plasma Glucose (PPG) Over a Standard Meal [Week 0, week 16]

   A standard meal contains 100g carbohydrate

3. Percentage of Participants Achieving the Treatment Target of HbA1c Below or Equal to 6.5% [Week 16]

4. Change in Fasting Serum Free Fatty Acid (FFA) From Baseline [Week 0, week 16]

5. Change in 2-hour Postprandial Serum Free Fatty Acid (FFA) Over a Standard Meal [Week 0, week 16]

6. Change in AUC0-180 of Serum Insulin Concentration of IVGTT (Intravenous Glucose Tolerance Test) [Over the course of three hours at Week 0 and Week 16]

7. Change in AUC0-180 of Plasma Glucose Concentration of IVGTT [Over the course of three hours at Week 0 and Week 16]

8. Number of All Treatment Emergent Hypoglycaemic Episodes [Weeks 0-16]

   A hypoglycaemic episode was defined as treatment emergent if the onset of the episode was on or after the first day of trial product and no later than the last day of the trial product.

9. Cholesterol [Week 0, week 16]

   The number of participants having a change in cholesterol from "normal" to "abnormal". "Abnormal" means a value of blood cholesterol is out of the normal range.

10. Change in Body Weight [Week 0, week 16]

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Type 2 diabetes

• Oral anti-diabetic drug (OAD) naïve (unsystematic OAD treatment 6 months prior to this trial is allowed)

• Insulin naïve (less than 1 week of daily use of insulin therapy before trial start is allowed)

• Lipid-lowing agent naïve

• HbA1c: 6.5-8.5%

• Fasting glucose: 6.1-13.0 mmol/L (110-234 mg/dl)

• Body Mass Index (BMI): 20-35 kg/m^2

• Be able and willing to perform self-monitored plasma glucose (SMPG)

• Be able and willing to eat 3 main meals per day

• Only applicable to subjects who will participate in the subgroup study: Be able and willing to perform and complete IVGTT (intravenous glucose tolerance test) at additional visits

Exclusion Criteria:

• Known or suspected allergy to repaglinide, gliclazide, or related products (for example sulfonamide or other sulphonylureas (SUs)), or any of the excipients in the study drugs

• Previous participation in this study

• Participation in a study of another investigational drug within 1 month prior to study start

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Shanghai	Shanghai	China	200025

Sponsors and Collaborators

• Novo Nordisk A/S

Investigators

• Study Director: Global Clinical Registry (GCR, 1452), Novo Nordisk A/S

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Clinical Trials at Novo Nordisk

Publications

None provided.

• Responsible Party: Novo Nordisk A/S
• ClinicalTrials.gov Identifier: NCT01022762
• Other Study ID Numbers: AGEE-3783; U1111-1111-9453
• First Posted: Dec 1, 2009
• Last Update Posted: Jul 9, 2014
• Last Verified: Jun 1, 2014

• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Repaglinide; Gliclazide

Study Results

Participant Flow

Recruitment Details	The trial was conducted at 23 sites in China.
Pre-assignment Detail	Between screening and treatment with trial drug the participants were assessed for eligibility and were randomised to one of two treatment arms. A sub-group of 69 participants was recruited for intravenous glucose tolerance test and randomised into the repaglinide treatment group (35 participants) and gliclazide treatment group (34 participants)

Arm/Group Title	Repaglinide	Gliclazide
Arm/Group Description	1 mg repaglinide twice daily (weeks 0-4), titrated (individually adjusted) to maintenance dose (weeks 4-16). Maximum dose is 4 mg three times daily	80 mg gliclazide once daily (weeks 0-4), titrated (individually adjusted) to maintenance dose (weeks 4-16). Maximum dose is 160 mg twice daily
Period Title: Overall Study
STARTED	218	222
Exposed to Trial Drug	217	218
COMPLETED	196	194
NOT COMPLETED	22	28

Baseline Characteristics

Arm/Group Title	Repaglinide	Gliclazide	Total
Arm/Group Description	1 mg repaglinide twice daily (weeks 0-4), titrated (individually adjusted) to maintenance dose (weeks 4-16). Maximum dose is 4 mg three times daily	80 mg gliclazide once daily (weeks 0-4), titrated (individually adjusted) to maintenance dose (weeks 4-16). Maximum dose is 160 mg twice daily	Total of all reporting groups
Overall Participants	217	218	435
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	54.1 (10.0)	53.5 (9.9)	53.8 (9.9)
Sex: Female, Male (Count of Participants)
Female	107 49.3%	95 43.6%	202 46.4%
Male	110 50.7%	123 56.4%	233 53.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	217 100%	218 100%	435 100%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	217 100%	218 100%	435 100%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	0 0%	0 0%	0 0%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
China	217 100%	218 100%	435 100%
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	163.2 (8.9)	163.9 (8.4)	163.5 (8.7)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	68.7 (11.6)	68.4 (11.2)	68.6 (11.4)
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	25.69 (3.00)	25.37 (3.01)	25.53 (3.00)
Duration of diagnosed diabetes (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	1.02 (1.95)	0.79 (1.82)	0.91 (1.89)

Outcome Measures

1. Primary Outcome

Title	Change in Glycosylated Haemoglobin (HbA1c)
Time Frame	Week 0, week 16

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) is randomised participants exposed to at least one dose of trial product after randomisation. Missing values were replaced with the last post-baseline data based on LOCF (last observation carried forward).

Arm/Group Title	Repaglinide	Gliclazide
Arm/Group Description	1 mg repaglinide twice daily (weeks 0-4), titrated (individually adjusted) to maintenance dose (weeks 4-16). Maximum dose is 4 mg three times daily	80 mg gliclazide once daily (weeks 0-4), titrated (individually adjusted) to maintenance dose (weeks 4-16). Maximum dose is 160 mg twice daily
Measure Participants	206	202
Least Squares Mean (Standard Error) [percentage (%) of total haemoglobin]	-0.857 (0.051)	-0.871 (0.051)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Repaglinide, Gliclazide
	Comments	H0: Change from baseline in HbA1c of repaglinide therapy at 16 weeks of treatment - change from baseline in HbA1c of gliclazide therapy at 16 weeks of treatment >= 0.4%. H1: Change from baseline in HbA1c of repaglinide therapy at 16 weeks of treatment - change from baseline in HbA1c of gliclazide therapy at 16 weeks of treatment < 0.4%. Sample size was calculated to achieve a power of at least 85%, assuming an equal change in HbA1c and a common standard deviation of 1.2%.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-inferiority would be shown if the upper limit of the 95% confidence interval was less than 0.4%. This corresponds to a one-sided test with a significance level of 2.5% of the hypothesis.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.014
	Confidence Interval	() 95%; -0.115 to 0.143
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.066
	Estimation Comments	If non-inferiority of repaglinide alone was shown, a test for superiority would be performed based on FAS. Superiority of repaglinide alone over gliclazide alone would be claimed if the upper limit of the 95% CI for the difference was lower than 0%.

2. Secondary Outcome

Title	Change in Fasting Plasma Glucose
Time Frame	Week 0, week 16

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) is randomised participants exposed to at least one dose of trial product after randomisation. Missing values were replaced with the last post-baseline data based on LOCF (last observation carried forward).

Arm/Group Title	Repaglinide	Gliclazide
Arm/Group Description	1 mg repaglinide twice daily (weeks 0-4), titrated (individually adjusted) to maintenance dose (weeks 4-16). Maximum dose is 4 mg three times daily	80 mg gliclazide once daily (weeks 0-4), titrated (individually adjusted) to maintenance dose (weeks 4-16). Maximum dose is 160 mg twice daily
Measure Participants	203	200
Least Squares Mean (Standard Error) [mmol/L]	-1.409 (0.104)	-1.667 (0.102)

3. Secondary Outcome

Title	Change in 2-hour Postprandial Plasma Glucose (PPG) Over a Standard Meal
Description	A standard meal contains 100g carbohydrate
Time Frame	Week 0, week 16

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) is randomised participants exposed to at least one dose of trial product after randomisation. Missing values were replaced with the last post-baseline data based on LOCF (last observation carried forward).

Arm/Group Title	Repaglinide	Gliclazide
Arm/Group Description	1 mg repaglinide twice daily (weeks 0-4), titrated (individually adjusted) to maintenance dose (weeks 4-16). Maximum dose is 4 mg three times daily	80 mg gliclazide once daily (weeks 0-4), titrated (individually adjusted) to maintenance dose (weeks 4-16). Maximum dose is 160 mg twice daily
Measure Participants	203	199
Least Squares Mean (Standard Error) [mmol/L]	-0.596 (0.215)	-0.699 (0.211)

4. Secondary Outcome

Title	Percentage of Participants Achieving the Treatment Target of HbA1c Below or Equal to 6.5%
Time Frame	Week 16

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) is randomised participants exposed to at least one dose of trial product after randomisation. Missing values were replaced with the last post-baseline data based on LOCF (last observation carried forward).

Arm/Group Title	Repaglinide	Gliclazide
Arm/Group Description	1 mg repaglinide twice daily (weeks 0-4), titrated (individually adjusted) to maintenance dose (weeks 4-16). Maximum dose is 4 mg three times daily	80 mg gliclazide once daily (weeks 0-4), titrated (individually adjusted) to maintenance dose (weeks 4-16). Maximum dose is 160 mg twice daily
Measure Participants	217	218
Number [percentage of participants]	62 28.6%	59 27.1%

5. Secondary Outcome

Title	Change in Fasting Serum Free Fatty Acid (FFA) From Baseline
Time Frame	Week 0, week 16

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) is randomised participants exposed to at least one dose of trial product after randomisation. Missing values were replaced with the last post-baseline data based on LOCF (last observation carried forward).

Arm/Group Title	Repaglinide	Gliclazide
Arm/Group Description	1 mg repaglinide twice daily (weeks 0-4), titrated (individually adjusted) to maintenance dose (weeks 4-16). Maximum dose is 4 mg three times daily	80 mg gliclazide once daily (weeks 0-4), titrated (individually adjusted) to maintenance dose (weeks 4-16). Maximum dose is 160 mg twice daily
Measure Participants	206	202
Least Squares Mean (Standard Error) [mmol/L]	-0.012 (0.014)	-0.02 (0.014)

6. Secondary Outcome

Title	Change in 2-hour Postprandial Serum Free Fatty Acid (FFA) Over a Standard Meal
Time Frame	Week 0, week 16

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) is randomised participants exposed to at least one dose of trial product after randomisation. Missing values were replaced with the last post-baseline data based on LOCF (last observation carried forward).

Arm/Group Title	Repaglinide	Gliclazide
Arm/Group Description	1 mg repaglinide twice daily (weeks 0-4), titrated (individually adjusted) to maintenance dose (weeks 4-16). Maximum dose is 4 mg three times daily	80 mg gliclazide once daily (weeks 0-4), titrated (individually adjusted) to maintenance dose (weeks 4-16). Maximum dose is 160 mg twice daily
Measure Participants	204	201
Least Squares Mean (Standard Error) [mmol/L]	-0.003 (0.007)	-0.004 (0.007)

7. Secondary Outcome

Title	Change in AUC0-180 of Serum Insulin Concentration of IVGTT (Intravenous Glucose Tolerance Test)
Time Frame	Over the course of three hours at Week 0 and Week 16

Outcome Measure Data

Analysis Population Description

A total of 69 participants were recruited into IVGTT, and were randomised into repaglinide treatment group (35 participants) and gliclazide treatment group (34 participants). Participants with eligible IVGTT profiles were included in IVGTT analysis set.

Arm/Group Title	Repaglinide	Gliclazide
Arm/Group Description	1 mg repaglinide twice daily (weeks 0-4), titrated (individually adjusted) to maintenance dose (weeks 4-16). Maximum dose is 4 mg three times daily	80 mg gliclazide once daily (weeks 0-4), titrated (individually adjusted) to maintenance dose (weeks 4-16). Maximum dose is 160 mg twice daily
Measure Participants	31	31
Mean (Standard Deviation) [min*pmol/L]	5139.55 (8720.80)	1426.21 (5262.15)

8. Secondary Outcome

Title	Change in AUC0-180 of Plasma Glucose Concentration of IVGTT
Time Frame	Over the course of three hours at Week 0 and Week 16

Outcome Measure Data

Analysis Population Description

A total of 69 participants were recruited into IVGTT, and were randomised into repaglinide treatment group (35 participants) and gliclazide treatment group (34 participants). Participants with eligible IVGTT profiles were included in IVGTT analysis set.

Arm/Group Title	Repaglinide	Gliclazide
Arm/Group Description	1 mg repaglinide twice daily (weeks 0-4), titrated (individually adjusted) to maintenance dose (weeks 4-16). Maximum dose is 4 mg three times daily	80 mg gliclazide once daily (weeks 0-4), titrated (individually adjusted) to maintenance dose (weeks 4-16). Maximum dose is 160 mg twice daily
Measure Participants	31	31
Mean (Standard Deviation) [min*mmol/L]	-272.30 (290.79)	-348.03 (258.86)

9. Secondary Outcome

Title	Number of All Treatment Emergent Hypoglycaemic Episodes
Description	A hypoglycaemic episode was defined as treatment emergent if the onset of the episode was on or after the first day of trial product and no later than the last day of the trial product.
Time Frame	Weeks 0-16

Outcome Measure Data

Analysis Population Description

Safety analysis set contains all randomised participants exposed to at least one dose of trial drug(s). One participant was randomised into repaglinide group, but was dispensed gliclazide from the very beginning of the study due to the investigator's negligence. This participant continued the gliclazide treatment until the end of the study.

Arm/Group Title	Repaglinide	Gliclazide
Arm/Group Description	1 mg repaglinide twice daily (weeks 0-4), titrated (individually adjusted) to maintenance dose (weeks 4-16). Maximum dose is 4 mg three times daily	80 mg gliclazide once daily (weeks 0-4), titrated (individually adjusted) to maintenance dose (weeks 4-16). Maximum dose is 160 mg twice daily
Measure Participants	216	219
Number [episodes]	165	147

10. Secondary Outcome

Title	Cholesterol
Description	The number of participants having a change in cholesterol from "normal" to "abnormal". "Abnormal" means a value of blood cholesterol is out of the normal range.
Time Frame	Week 0, week 16

Outcome Measure Data

Analysis Population Description

Safety analysis set contains all randomised participants exposed to at least one dose of trial drug(s)

Arm/Group Title	Repaglinide	Gliclazide
Arm/Group Description	1 mg repaglinide twice daily (weeks 0-4), titrated (individually adjusted) to maintenance dose (weeks 4-16). Maximum dose is 4 mg three times daily	80 mg gliclazide once daily (weeks 0-4), titrated (individually adjusted) to maintenance dose (weeks 4-16). Maximum dose is 160 mg twice daily
Measure Participants	216	219
Number [participants]	18 8.3%	11 5%

11. Secondary Outcome

Title	Change in Body Weight
Time Frame	Week 0, week 16

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) is randomised participants exposed to at least one dose of trial product after randomisation

Arm/Group Title	Repaglinide	Gliclazide
Arm/Group Description	1 mg repaglinide twice daily (weeks 0-4), titrated (individually adjusted) to maintenance dose (weeks 4-16). Maximum dose is 4 mg three times daily	80 mg gliclazide once daily (weeks 0-4), titrated (individually adjusted) to maintenance dose (weeks 4-16). Maximum dose is 160 mg twice daily
Measure Participants	196	194
Least Squares Mean (Standard Error) [kg]	-0.750 (0.218)	-0.511 (0.215)

Adverse Events

Time Frame	The adverse events were collected in a timespan of 16 weeks.
Adverse Event Reporting Description	Safety analysis set contains all randomised participants exposed to at least one dose of trial drug(s).
Arm/Group Title	Repaglinide		Gliclazide
Arm/Group Description	1 mg repaglinide twice daily (weeks 0-4), titrated (individually adjusted) to maintenance dose (weeks 4-16). Maximum dose is 4 mg three times daily		80 mg gliclazide once daily (weeks 0-4), titrated (individually adjusted) to maintenance dose (weeks 4-16). Maximum dose is 160 mg twice daily
All Cause Mortality
	Repaglinide		Gliclazide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Repaglinide		Gliclazide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/216 (1.4%)		0/219 (0%)
Gastrointestinal disorders
Haemorrhoidal haemorrhage	1/216 (0.5%)	1	0/219 (0%)	0
Musculoskeletal and connective tissue disorders
Intervertebral Disc Protrusion	1/216 (0.5%)	1	0/219 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Gall bladder cancer	1/216 (0.5%)	1	0/219 (0%)	0
Other (Not Including Serious) Adverse Events
	Repaglinide		Gliclazide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/216 (0%)		0/219 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Novo Nordisk reserves the right to not release data until specified milestones, e.g. when the clinical trial report is available. This includes the right to not release interim results of clinical trials. At the end of the trial, one or more manuscripts for publication will be prepared collaboratively between Investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or communication for less than 60 days to protect intellectual property.