Comparison of the Blood Sugar Lowering Effect Between Repaglinide Plus Metformin and Repaglinide Alone in Type 2 Diabetics Not Previously Treated With Oral Sugar-lowering Drugs

• Sponsor: Novo Nordisk A/S (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00819741
• Collaborator: (none)
• Enrollment: 433
• Locations: 17
• Arms: 2
• Duration (Months): 9
• Patients Per Site: 25.5
• Patients Per Site Per Month: 2.8

Study Details

Study Description

Brief Summary

This trial is conducted in Asia. The aim of this clinical trial is to investigate the blood sugar lowering effect of repaglinide plus metformin as initial treatment compared to repaglinide alone in Chinese subjects with type 2 diabetes having an HbA1c (glycosylated haemoglobin A1c) over 8.5 % and who never have taken oral sugar-lowering drugs before. The associated unfavourable events including low blood sugar episodes between the two treatments are also compared.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 433 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A 16-week, Open-label, Multicentre, Randomised, Parallel Study to Evaluate Efficacy and Safety of Repaglinide and Metformin Combination Therapy Compared to Repaglinide Monotherapy in Chinese OAD Naive Type 2 Diabetic Patients
• Study Start Date: Feb 1, 2009
• Actual Primary Completion Date: Nov 1, 2009
• Actual Study Completion Date: Nov 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Repaglinide + metformin Initial dose of repaglinide 1mg plus metformin 500mg once daily. During the dose titration period of 6 weeks, the dose could be titrated up to repaglinide 4 mg and metformin 500 mg three times daily, according to fasting glucose values. The minimal dose was repaglinide 1 mg plus metformin 500 mg three times daily.	Drug: repaglinide; The dose was started from repaglinide 1 mg plus metformin 500 mg once daily. During the dose titration period, the dose could be titrated up to repaglinide 4 mg and metformin 500mg three times daily, according to fasting glucose. the minimal dose was repaglinide 1 mg plus metformin 500 mg three times daily; Drug: metformin; The dose was started from repaglinide 1 mg plus metformin 500 mg once daily. During the dose titration period, the dose could be titrated up to repaglinide 4 mg and metformin 500 mg three times daily, according to fasting glucose. the minimal dose was repaglinide 1 mg plus metformin 500 mg three times daily
Active Comparator: Repaglinide Initial dose of repaglinide 1 mg three times daily. During the dose titration period of 6 weeks, the dose of repaglinide could be titrated up to 4 mg three times daily, according to fasting glucose values. The minimal dose was repaglinide 1 mg three times daily.	Drug: repaglinide; The dose was started from repaglinide 1 mg three times daily. During the dose titration period, the dose of repaglinide could be titrated up to 4 mg three times daily, according to fasting glucose.

Outcome Measures

Primary Outcome Measures

1. Change in Glycosylated Haemoglobin A1c (HbA1c) [week -2 (screening), week 16]

   Calculated as an estimate of the mean change in HbA1c after 16 weeks of treatment.

Secondary Outcome Measures

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

   Calculated as an estimate of the mean change in fasting plasma glucose after 16 weeks of treatment.

2. Change in 2-hour Postprandial Plasma Glucose [Week 0, week 16]

   Calculated as an estimate of the mean change in 2-hour postprandial plasma glucose following a standard test meal after 16 weeks of treatment

3. Change in 7-point Plasma Glucose Profile [Week 0, week 16]

   Calculated as an estimate of the mean change in 7-point (before breakfast, 2 hours after breakfast, before lunch, 2 hours after lunch, before dinner, 2 hours after dinner, bedtime) plasma glucose profile after 16 weeks of treatment.

4. Change in Fasting Serum Insulin [Week 0, week 16]

   Calculated as an estimate of the mean change in fasting serum insulin after 16 weeks of treatment.

5. Change in 2-hour Postprandial Serum Insulin [Week 0, week 16]

   Calculated as an estimate of the mean change in 2-hour postprandial serum insulin after 16 weeks of treatment.

6. Change in Fasting Serum C-peptide [Week 0, week 16]

   Calculated as an estimate of the mean change in fasting serum C-peptide after 16 weeks of treatment

7. Change in 2-hour Postprandial Serum C-peptide [Week 0, week 16]

   Calculated as an estimate of the mean change in 2-hour postprandial serum C-peptide after 16 weeks of treatment

8. Hypoglycaemic Episodes [Weeks 0-16]

   Number of hypoglycaemic episodes from Week 0 to Week 16, defined as major, minor or symptoms only. Major if unable to treat her/himself. Minor if able to treat her/himself and plasma glucose below 3.1 mmol/L. Symptoms only if able to treat her/himself and no plasma glucose measurement or plasma glucose higher than or equal to 3.1 mmol/L.

9. Change in Blood Pressure [Week 0, week 16]

   Calculated as the mean change in diastolic and systolic blood pressure after 16 weeks of treatment

10. Physical Examinations [Week -2, week 16]

    The number of subjects having a physical examination event that changed from 'Normal' or 'Abnormal, not clinically significant' to 'Abnormal, clinically significant'. Physical examination included cardiovascular system, respiratory system, musculoskeletal system, nervous system and abdomen.

11. ECG (ElectroCardioGram) [Week -2, week 16]

    The number of subjects having a electrocardiogram (ECG) that changed from 'Normal' or 'Abnormal, not clinically significant' to 'Abnormal, clinically significant'. 'Abnormal, Clinically significant' is an abnormality that suggests a disease and/or organ toxicity and is of a severity, which requires active management.

12. Biochemistry: Alanine Aminotransferase (ALAT) [Week -2, week 16]

    The number of subjects having a change in Alanine Aminotransferase (ALAT) from 'Normal' or 'Abnormal, not clinically significant' to 'Abnormal, clinically significant'. 'Abnormal, Clinically significant' is an abnormality that suggests a disease and/or organ toxicity and is of a severity, which requires active management.

13. Biochemistry: Alanine Aminotransferase (ASAT) [Week -2, week 16]

    The number of subjects having a change in Aspartate Aminotransferase (ASAT) from 'Normal' or 'Abnormal, not clinically significant' to 'Abnormal, clinically significant'. 'Abnormal, Clinically significant' is an abnormality that suggests a disease and/or organ toxicity and is of a severity, which requires active management.

14. Haematology: Haemoglobin [Week -2, week 16]

    Haemoglobin was measured. The number of subjects having a change in Haemoglobin measurement from 'Normal' or 'Abnormal, not clinically significant' to 'Abnormal, clinically significant' 'Abnormal, Clinically significant' is an abnormality that suggests a disease and/or organ toxicity and is of a severity, which requires active management.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Diagnosed with type 2 diabetes

• Never taken oral antidiabetic drugs before

• HbA1c greater than 8.5 %

• BMI (Body Mass Index) less than or equal to 35 kg/m^2

Exclusion Criteria:

• Known or suspected allergy to repaglinide, metformin, or any of the excipients in the medications

• Taken an investigational drug in another clinical trial within 4 weeks prior to this trial

• Impaired liver function, defined as ASAT (aspartate aminotransferase) or ALAT (alanine aminotransferase) equal to or greater than 2 times upper normal limit

• Have a clinically significant, active disease of the gastrointestinal, pulmonary, neurological, renal, genitourinary, and haematological systems

• Severe uncontrolled or untreated hypertension (sitting diastolic blood pressure (BP) equal to or greater than 100 mmHg or systolic BP equal to or greater than 180 mmHg)

• Impaired renal function

• Acute or chronic acidosis or if there are plans to have a radiographic material containing iodine

• Have a clinically significant, active cardiovascular disease, or decompensated heart failure

• Treatment with systemic corticosteroids within the past two months prior to screening

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novo Nordisk Investigational Site	Fuzhou	Fujian	China	350001
2	Novo Nordisk Investigational Site	Nanjing	Jiangsu	China	210009
3	Novo Nordisk Investigational Site	Nanjing	Jiangsu	China	210012
4	Novo Nordisk Investigational Site	Nanjing	Jiangsu	China	210029
5	Novo Nordisk Investigational Site	Suzhou	Jiangsu	China	215004
6	Novo Nordisk Investigational Site	Wuxi	Jiangsu	China	214023
7	Novo Nordisk Investigational Site	Nanchang	Jiangxi	China	330006
8	Novo Nordisk Investigational Site	Shanghai	Shanghai	China	200001
9	Novo Nordisk Investigational Site	Shanghai	Shanghai	China	200025
10	Novo Nordisk Investigational Site	Shanghai	Shanghai	China	200072
11	Novo Nordisk Investigational Site	Shanghai	Shanghai	China	200092
12	Novo Nordisk Investigational Site	Shanghai	Shanghai	China	200120
13	Novo Nordisk Investigational Site	Hangzhou	Zhejiang	China	310003
14	Novo Nordisk Investigational Site	Wenzhou	Zhejiang	China	325000
15	Novo Nordisk Investigational Site	Hangzhou		China	310016
16	Novo Nordisk Investigational Site	Nantong		China	226001
17	Novo Nordisk Investigational Site	Shanghai		China	200040

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: NCT00819741
• Other Study ID Numbers: AGEE-3705
• First Posted: Jan 9, 2009
• Last Update Posted: Feb 10, 2017
• Last Verified: Dec 1, 2016

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

Study Results

Participant Flow

Recruitment Details	The trial was conducted at 17 sites in China.
Pre-assignment Detail	Between screening and treatment with trial drug, subjects were assessed for eligibility and were randomised to one of two treatment arms. After start of treatment, all the subjects underwent a 6-week dose titration period followed by a 10-week maintenance period. A subgroup of 50 subjects from each treatment group was chosen.

Arm/Group Title	Repaglinide + Metformin	Repaglinide
Arm/Group Description	Initial dose of repaglinide 1mg plus metformin 500mg once daily. During the dose titration period of 6 weeks, the dose could be titrated up to repaglinide 4 mg and metformin 500 mg three times daily, according to fasting glucose values. The minimal dose was repaglinide 1 mg plus metformin 500 mg three times daily.	Initial dose of repaglinide 1 mg three times daily. During the dose titration period of 6 weeks, the dose of repaglinide could be titrated up to 4 mg three times daily, according to fasting glucose values. The minimal dose was repaglinide 1 mg three times daily.
Period Title: Overall Study
STARTED	218	215
Exposed to Drug	218	214
COMPLETED	196	201
NOT COMPLETED	22	14

Baseline Characteristics

Arm/Group Title	Repaglinide + Metformin	Repaglinide	Total
Arm/Group Description	Initial dose of repaglinide 1mg plus metformin 500mg once daily. During the dose titration period of 6 weeks, the dose could be titrated up to repaglinide 4 mg and metformin 500 mg three times daily, according to fasting glucose values. The minimal dose was repaglinide 1 mg plus metformin 500 mg three times daily.	Initial dose of repaglinide 1 mg three times daily. During the dose titration period of 6 weeks, the dose of repaglinide could be titrated up to 4 mg three times daily, according to fasting glucose values. The minimal dose was repaglinide 1 mg three times daily.	Total of all reporting groups
Overall Participants	218	214	432
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	50.4 (9.6)	49.4 (10.0)	49.9 (10.0)
Gender (Count of Participants)
Female	60 27.5%	59 27.6%	119 27.5%
Male	158 72.5%	155 72.4%	313 72.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	218 100%	214 100%	432 100%
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%
BMI (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	24.50 (2.97)	24.44 (3.05)	24.47 (3.00)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	68.3 (10.8)	68.2 (11.0)	68.3 (10.9)
Duration of diabetes (months) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [months]	0.14 (0.73)	0.28 (1.57)	0.21 (1.22)
HbA1c (percentage (%) of total haemoglobin) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percentage (%) of total haemoglobin]	10.91 (1.45)	10.73 (1.50)	10.82 (1.48)

Outcome Measures

1. Primary Outcome

Title	Change in Glycosylated Haemoglobin A1c (HbA1c)
Description	Calculated as an estimate of the mean change in HbA1c after 16 weeks of treatment.
Time Frame	week -2 (screening), week 16

Outcome Measure Data

Analysis Population Description

Intention-to-Treat analysis set (ITT) is all subjects who entered the trial treatment period and exposed to at least one dose of trial product.

Arm/Group Title	Repaglinide + Metformin	Repaglinide
Arm/Group Description	Initial dose of repaglinide 1mg plus metformin 500mg once daily. During the dose titration period of 6 weeks, the dose could be titrated up to repaglinide 4 mg and metformin 500 mg three times daily, according to fasting glucose values. The minimal dose was repaglinide 1 mg plus metformin 500 mg three times daily.	Initial dose of repaglinide 1 mg three times daily. During the dose titration period of 6 weeks, the dose of repaglinide could be titrated up to 4 mg three times daily, according to fasting glucose values. The minimal dose was repaglinide 1 mg three times daily.
Measure Participants	212	209
Least Squares Mean (Standard Error) [percentage (%) of total haemoglobin]	-4.450 (0.070)	-4.148 (0.071)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Repaglinide + Metformin, Repaglinide
	Comments	The non-inferiority margin for HbA1c was set to 0.4%. The null hypothesis (H0) was: H0: HbA1c of repaglinide + metformin therapy after 16 weeks of treatment - HbA1c of repaglinide monotherapy after 16 weeks of treatment ≥0.4% Against the alternative hypothesis (H1): H1: HbA1c of repaglinide + metformin therapy after 16 weeks of treatment - HbA1c of repaglinide monotherapy after 16 weeks of treatment <0.4%
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	If non-inferiority was shown (that was if H0 was rejected), then superiority of repaglinide and metformin combination therapy compared to repaglinide monotherapy would be claimed if the upper limit of the 95% CI for the difference was lower than 0%. The non-inferiority margin for HbA1c was set to 0.4%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Estimated treatment difference, LS Mean
	Estimated Value	-0.302
	Confidence Interval	() 95%; -0.491 to -0.114
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.0096
	Estimation Comments

2. Secondary Outcome

Title	Change in Fasting Plasma Glucose
Description	Calculated as an estimate of the mean change in fasting plasma glucose after 16 weeks of treatment.
Time Frame	week 0, week 16

Outcome Measure Data

Analysis Population Description

Intention-to-Treat analysis set (ITT) is all subjects who entered the trial treatment period and exposed to at least one dose of trial product.

Arm/Group Title	Repaglinide + Metformin	Repaglinide
Arm/Group Description	Initial dose of repaglinide 1mg plus metformin 500mg once daily. During the dose titration period of 6 weeks, the dose could be titrated up to repaglinide 4 mg and metformin 500 mg three times daily, according to fasting glucose values. The minimal dose was repaglinide 1 mg plus metformin 500 mg three times daily.	Initial dose of repaglinide 1 mg three times daily. During the dose titration period of 6 weeks, the dose of repaglinide could be titrated up to 4 mg three times daily, according to fasting glucose values. The minimal dose was repaglinide 1 mg three times daily.
Measure Participants	211	209
Least Squares Mean (Standard Error) [mmol/L]	-4.646 (0.129)	-3.982 (0.130)

3. Secondary Outcome

Title	Change in 2-hour Postprandial Plasma Glucose
Description	Calculated as an estimate of the mean change in 2-hour postprandial plasma glucose following a standard test meal after 16 weeks of treatment
Time Frame	Week 0, week 16

Outcome Measure Data

Analysis Population Description

Intention-to-Treat analysis set (ITT) is all subjects who entered the trial treatment period and exposed to at least one dose of trial product.

Arm/Group Title	Repaglinide + Metformin	Repaglinide
Arm/Group Description	Initial dose of repaglinide 1mg plus metformin 500mg once daily. During the dose titration period of 6 weeks, the dose could be titrated up to repaglinide 4 mg and metformin 500 mg three times daily, according to fasting glucose values. The minimal dose was repaglinide 1 mg plus metformin 500 mg three times daily.	Initial dose of repaglinide 1 mg three times daily. During the dose titration period of 6 weeks, the dose of repaglinide could be titrated up to 4 mg three times daily, according to fasting glucose values. The minimal dose was repaglinide 1 mg three times daily.
Measure Participants	210	204
Least Squares Mean (Standard Error) [mmol/L]	-7.525 (0.237)	-6.794 (0.242)

4. Secondary Outcome

Title	Change in 7-point Plasma Glucose Profile
Description	Calculated as an estimate of the mean change in 7-point (before breakfast, 2 hours after breakfast, before lunch, 2 hours after lunch, before dinner, 2 hours after dinner, bedtime) plasma glucose profile after 16 weeks of treatment.
Time Frame	Week 0, week 16

Outcome Measure Data

Analysis Population Description

Intention-to-Treat analysis set (ITT) is all subjects who entered the trial treatment period and exposed to at least one dose of trial product.

Arm/Group Title	Repaglinide + Metformin	Repaglinide
Arm/Group Description	Initial dose of repaglinide 1mg plus metformin 500mg once daily. During the dose titration period of 6 weeks, the dose could be titrated up to repaglinide 4 mg and metformin 500 mg three times daily, according to fasting glucose values. The minimal dose was repaglinide 1 mg plus metformin 500 mg three times daily.	Initial dose of repaglinide 1 mg three times daily. During the dose titration period of 6 weeks, the dose of repaglinide could be titrated up to 4 mg three times daily, according to fasting glucose values. The minimal dose was repaglinide 1 mg three times daily.
Measure Participants	218	214
Before breakfast, N=204, 199	-4.99 (0.11)	-4.58 (0.12)
2 hours after breakfast, N=206, 201	-7.85 (0.23)	-7.40 (0.24)
Before lunch, N=203, 200	-6.85 (0.18)	-6.28 (0.18)
2 hours after lunch, N=204, 201	-8.00 (0.21)	-6.98 (0.21)
Before dinner N=204, 202	-5.62 (0.17)	-5.09 (0.17)
2 hours after dinner N=204, 199	-7.13 (0.21)	-5.70 (0.22)
Bedtime N=195, 188	-6.93 (0.19)	-5.82 (0.19)
Average N=207, 202	-6.78 (0.14)	-5.99 (0.14)

5. Secondary Outcome

Title	Change in Fasting Serum Insulin
Description	Calculated as an estimate of the mean change in fasting serum insulin after 16 weeks of treatment.
Time Frame	Week 0, week 16

Outcome Measure Data

Analysis Population Description

Intention-to-Treat analysis set (ITT) is all subjects who entered the trial treatment period and exposed to at least one dose of trial product. A total of 100 subjects (50 per study group) out of the total subjects were randomly selected in the trial. Four trial sites were selected for the subgroup study.

Arm/Group Title	Repaglinide + Metformin	Repaglinide
Arm/Group Description	Initial dose of repaglinide 1mg plus metformin 500mg once daily. During the dose titration period of 6 weeks, the dose could be titrated up to repaglinide 4 mg and metformin 500 mg three times daily, according to fasting glucose values. The minimal dose was repaglinide 1 mg plus metformin 500 mg three times daily.	Initial dose of repaglinide 1 mg three times daily. During the dose titration period of 6 weeks, the dose of repaglinide could be titrated up to 4 mg three times daily, according to fasting glucose values. The minimal dose was repaglinide 1 mg three times daily.
Measure Participants	49	46
Least Squares Mean (Standard Error) [mU/L]	3.163 (1.801)	5.694 (1.872)

6. Secondary Outcome

Title	Change in 2-hour Postprandial Serum Insulin
Description	Calculated as an estimate of the mean change in 2-hour postprandial serum insulin after 16 weeks of treatment.
Time Frame	Week 0, week 16

Outcome Measure Data

Analysis Population Description

Intention-to-Treat analysis set (ITT) is all subjects who entered the trial treatment period and exposed to at least one dose of trial product. A total of 100 subjects (50 per study group) out of the total subjects were randomly selected in the trial. Four trial sites were selected for the subgroup study.

Arm/Group Title	Repaglinide + Metformin	Repaglinide
Arm/Group Description	Initial dose of repaglinide 1mg plus metformin 500mg once daily. During the dose titration period of 6 weeks, the dose could be titrated up to repaglinide 4 mg and metformin 500 mg three times daily, according to fasting glucose values. The minimal dose was repaglinide 1 mg plus metformin 500 mg three times daily.	Initial dose of repaglinide 1 mg three times daily. During the dose titration period of 6 weeks, the dose of repaglinide could be titrated up to 4 mg three times daily, according to fasting glucose values. The minimal dose was repaglinide 1 mg three times daily.
Measure Participants	49	44
Least Squares Mean (Standard Error) [mU/L]	34.083 (6.731)	28.548 (7.132)

7. Secondary Outcome

Title	Change in Fasting Serum C-peptide
Description	Calculated as an estimate of the mean change in fasting serum C-peptide after 16 weeks of treatment
Time Frame	Week 0, week 16

Outcome Measure Data

Analysis Population Description

Intention-to-Treat analysis set (ITT) is all subjects who entered the trial treatment period and exposed to at least one dose of trial product. A total of 100 subjects (50 per study group) out of the total subjects were randomly selected in the trial. Four trial sites were selected for the subgroup study.

Arm/Group Title	Repaglinide + Metformin	Repaglinide
Arm/Group Description	Initial dose of repaglinide 1mg plus metformin 500mg once daily. During the dose titration period of 6 weeks, the dose could be titrated up to repaglinide 4 mg and metformin 500 mg three times daily, according to fasting glucose values. The minimal dose was repaglinide 1 mg plus metformin 500 mg three times daily.	Initial dose of repaglinide 1 mg three times daily. During the dose titration period of 6 weeks, the dose of repaglinide could be titrated up to 4 mg three times daily, according to fasting glucose values. The minimal dose was repaglinide 1 mg three times daily.
Measure Participants	49	46
Least Squares Mean (Standard Error) [ng/ml]	0.041 (0.123)	0.405 (0.128)

8. Secondary Outcome

Title	Change in 2-hour Postprandial Serum C-peptide
Description	Calculated as an estimate of the mean change in 2-hour postprandial serum C-peptide after 16 weeks of treatment
Time Frame	Week 0, week 16

Outcome Measure Data

Analysis Population Description

Intention-to-Treat analysis set (ITT) is all subjects who entered the trial treatment period and exposed to at least one dose of trial product. A total of 100 subjects (50 per study group) out of the total subjects were randomly selected in the trial. Four trial sites were selected for the subgroup study.

Arm/Group Title	Repaglinide + Metformin	Repaglinide
Arm/Group Description	Initial dose of repaglinide 1mg plus metformin 500mg once daily. During the dose titration period of 6 weeks, the dose could be titrated up to repaglinide 4 mg and metformin 500 mg three times daily, according to fasting glucose values. The minimal dose was repaglinide 1 mg plus metformin 500 mg three times daily.	Initial dose of repaglinide 1 mg three times daily. During the dose titration period of 6 weeks, the dose of repaglinide could be titrated up to 4 mg three times daily, according to fasting glucose values. The minimal dose was repaglinide 1 mg three times daily.
Measure Participants	49	44
Least Squares Mean (Standard Error) [ng/ml]	2.301 (0.347)	2.081 (0.369)

9. Secondary Outcome

Title	Hypoglycaemic Episodes
Description	Number of hypoglycaemic episodes from Week 0 to Week 16, defined as major, minor or symptoms only. Major if unable to treat her/himself. Minor if able to treat her/himself and plasma glucose below 3.1 mmol/L. Symptoms only if able to treat her/himself and no plasma glucose measurement or plasma glucose higher than or equal to 3.1 mmol/L.
Time Frame	Weeks 0-16

Outcome Measure Data

Analysis Population Description

Safety analysis set was defined as all randomised and exposed subjects.

Arm/Group Title	Repaglinide + Metformin	Repaglinide
Arm/Group Description	Initial dose of repaglinide 1mg plus metformin 500mg once daily. During the dose titration period of 6 weeks, the dose could be titrated up to repaglinide 4 mg and metformin 500 mg three times daily, according to fasting glucose values. The minimal dose was repaglinide 1 mg plus metformin 500 mg three times daily.	Initial dose of repaglinide 1 mg three times daily. During the dose titration period of 6 weeks, the dose of repaglinide could be titrated up to 4 mg three times daily, according to fasting glucose values. The minimal dose was repaglinide 1 mg three times daily.
Measure Participants	218	214
Major	0	0
Minor	41	16
Symptoms only	90	71

10. Secondary Outcome

Title	Change in Blood Pressure
Description	Calculated as the mean change in diastolic and systolic blood pressure after 16 weeks of treatment
Time Frame	Week 0, week 16

Outcome Measure Data

Analysis Population Description

Safety analysis set was defined as all randomised and exposed subjects.

Arm/Group Title	Repaglinide + Metformin	Repaglinide
Arm/Group Description	Initial dose of repaglinide 1mg plus metformin 500mg once daily. During the dose titration period of 6 weeks, the dose could be titrated up to repaglinide 4 mg and metformin 500 mg three times daily, according to fasting glucose values. The minimal dose was repaglinide 1 mg plus metformin 500 mg three times daily.	Initial dose of repaglinide 1 mg three times daily. During the dose titration period of 6 weeks, the dose of repaglinide could be titrated up to 4 mg three times daily, according to fasting glucose values. The minimal dose was repaglinide 1 mg three times daily.
Measure Participants	196	201
Blood pressure diastolic	-1.0 (8.8)	-0.9 (9.5)
Blood pressure systolic	-1.5 (14.3)	-1.4 (14.2)

11. Secondary Outcome

Title	Physical Examinations
Description	The number of subjects having a physical examination event that changed from 'Normal' or 'Abnormal, not clinically significant' to 'Abnormal, clinically significant'. Physical examination included cardiovascular system, respiratory system, musculoskeletal system, nervous system and abdomen.
Time Frame	Week -2, week 16

Outcome Measure Data

Analysis Population Description

Safety analysis set was defined as all randomised and exposed subjects.

Arm/Group Title	Repaglinide + Metformin	Repaglinide
Arm/Group Description	Initial dose of repaglinide 1mg plus metformin 500mg once daily. During the dose titration period of 6 weeks, the dose could be titrated up to repaglinide 4 mg and metformin 500 mg three times daily, according to fasting glucose values. The minimal dose was repaglinide 1 mg plus metformin 500 mg three times daily.	Initial dose of repaglinide 1 mg three times daily. During the dose titration period of 6 weeks, the dose of repaglinide could be titrated up to 4 mg three times daily, according to fasting glucose values. The minimal dose was repaglinide 1 mg three times daily.
Measure Participants	218	214
Number [Subjects]	3	0

12. Secondary Outcome

Title	ECG (ElectroCardioGram)
Description	The number of subjects having a electrocardiogram (ECG) that changed from 'Normal' or 'Abnormal, not clinically significant' to 'Abnormal, clinically significant'. 'Abnormal, Clinically significant' is an abnormality that suggests a disease and/or organ toxicity and is of a severity, which requires active management.
Time Frame	Week -2, week 16

Outcome Measure Data

Analysis Population Description

Safety analysis set was defined as all randomised and exposed subjects.

Arm/Group Title	Repaglinide + Metformin	Repaglinide
Arm/Group Description	Initial dose of repaglinide 1mg plus metformin 500mg once daily. During the dose titration period of 6 weeks, the dose could be titrated up to repaglinide 4 mg and metformin 500 mg three times daily, according to fasting glucose values. The minimal dose was repaglinide 1 mg plus metformin 500 mg three times daily.	Initial dose of repaglinide 1 mg three times daily. During the dose titration period of 6 weeks, the dose of repaglinide could be titrated up to 4 mg three times daily, according to fasting glucose values. The minimal dose was repaglinide 1 mg three times daily.
Measure Participants	218	214
Number [Subjects]	3	2

13. Secondary Outcome

Title	Biochemistry: Alanine Aminotransferase (ALAT)
Description	The number of subjects having a change in Alanine Aminotransferase (ALAT) from 'Normal' or 'Abnormal, not clinically significant' to 'Abnormal, clinically significant'. 'Abnormal, Clinically significant' is an abnormality that suggests a disease and/or organ toxicity and is of a severity, which requires active management.
Time Frame	Week -2, week 16

Outcome Measure Data

Analysis Population Description

Safety analysis set was defined as all randomised and exposed subjects.

Arm/Group Title	Repaglinide + Metformin	Repaglinide
Arm/Group Description	Initial dose of repaglinide 1mg plus metformin 500mg once daily. During the dose titration period of 6 weeks, the dose could be titrated up to repaglinide 4 mg and metformin 500 mg three times daily, according to fasting glucose values. The minimal dose was repaglinide 1 mg plus metformin 500 mg three times daily.	Initial dose of repaglinide 1 mg three times daily. During the dose titration period of 6 weeks, the dose of repaglinide could be titrated up to 4 mg three times daily, according to fasting glucose values. The minimal dose was repaglinide 1 mg three times daily.
Measure Participants	218	214
Number [Subjects]	4	5

14. Secondary Outcome

Title	Biochemistry: Alanine Aminotransferase (ASAT)
Description	The number of subjects having a change in Aspartate Aminotransferase (ASAT) from 'Normal' or 'Abnormal, not clinically significant' to 'Abnormal, clinically significant'. 'Abnormal, Clinically significant' is an abnormality that suggests a disease and/or organ toxicity and is of a severity, which requires active management.
Time Frame	Week -2, week 16

Outcome Measure Data

Analysis Population Description

Safety analysis set was defined as all randomised and exposed subjects.

Arm/Group Title	Repaglinide + Metformin	Repaglinide
Arm/Group Description	Initial dose of repaglinide 1mg plus metformin 500mg once daily. During the dose titration period of 6 weeks, the dose could be titrated up to repaglinide 4 mg and metformin 500 mg three times daily, according to fasting glucose values. The minimal dose was repaglinide 1 mg plus metformin 500 mg three times daily.	Initial dose of repaglinide 1 mg three times daily. During the dose titration period of 6 weeks, the dose of repaglinide could be titrated up to 4 mg three times daily, according to fasting glucose values. The minimal dose was repaglinide 1 mg three times daily.
Measure Participants	218	214
Number [Subjects]	2	4

15. Secondary Outcome

Title	Haematology: Haemoglobin
Description	Haemoglobin was measured. The number of subjects having a change in Haemoglobin measurement from 'Normal' or 'Abnormal, not clinically significant' to 'Abnormal, clinically significant' 'Abnormal, Clinically significant' is an abnormality that suggests a disease and/or organ toxicity and is of a severity, which requires active management.
Time Frame	Week -2, week 16

Outcome Measure Data

Analysis Population Description

Safety analysis set was defined as all randomised and exposed subjects.

Arm/Group Title	Repaglinide + Metformin	Repaglinide
Arm/Group Description	Initial dose of repaglinide 1mg plus metformin 500mg once daily. During the dose titration period of 6 weeks, the dose could be titrated up to repaglinide 4 mg and metformin 500 mg three times daily, according to fasting glucose values. The minimal dose was repaglinide 1 mg plus metformin 500 mg three times daily.	Initial dose of repaglinide 1 mg three times daily. During the dose titration period of 6 weeks, the dose of repaglinide could be titrated up to 4 mg three times daily, according to fasting glucose values. The minimal dose was repaglinide 1 mg three times daily.
Measure Participants	218	214
Number [Subjects]	1	0

Adverse Events

Time Frame	The adverse events were collected in a time span of 16 weeks.
Adverse Event Reporting Description	The safety analysis set contains all randomised subjects exposed to at least one dose of trial drug(s).
Arm/Group Title	Repaglinide + Metformin		Repaglinide
Arm/Group Description	Initial dose of repaglinide 1mg plus metformin 500mg once daily. During the dose titration period of 6 weeks, the dose could be titrated up to repaglinide 4 mg and metformin 500 mg three times daily, according to fasting glucose values. The minimal dose was repaglinide 1 mg plus metformin 500 mg three times daily.		Initial dose of repaglinide 1 mg three times daily. During the dose titration period of 6 weeks, the dose of repaglinide could be titrated up to 4 mg three times daily, according to fasting glucose values. The minimal dose was repaglinide 1 mg three times daily.
All Cause Mortality
	Repaglinide + Metformin		Repaglinide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Repaglinide + Metformin		Repaglinide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/218 (0%)		1/214 (0.5%)
Psychiatric disorders
Anxiety	0/218 (0%)	0	1/214 (0.5%)	1
Other (Not Including Serious) Adverse Events
	Repaglinide + Metformin		Repaglinide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/218 (0%)		0/214 (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. 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.