Diabetes, Diabetes Mellitus, Type 2
Conditions
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.
Interventions
DRUGrepaglinide
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
DRUGmetformin
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
Sponsors
Novo Nordisk A/S
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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. |
| 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. |
| 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. |
| 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 |
| 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 |
| 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. |
| Change in Blood Pressure | Week 0, week 16 | Calculated as the mean change in diastolic and systolic blood pressure after 16 weeks of treatment |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
Countries
China
Participant flow
Recruitment details
The trial was conducted at 17 sites in China.
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 218 |
| 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. | 214 |
| Total | 432 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 5 | 2 |
| Overall Study | Lack of Efficacy | 0 | 2 |
| Overall Study | Lost to Follow-up | 3 | 1 |
| Overall Study | Protocol Violation | 3 | 4 |
| Overall Study | Reasons unknown | 3 | 3 |
| Overall Study | Unclassified | 6 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 2 |
Baseline characteristics
| Characteristic | Repaglinide | Total | Repaglinide + Metformin |
|---|---|---|---|
| Age, Continuous | 49.4 years STANDARD_DEVIATION 10 | 49.9 years STANDARD_DEVIATION 10 | 50.4 years STANDARD_DEVIATION 9.6 |
| BMI | 24.44 kg/m^2 STANDARD_DEVIATION 3.05 | 24.47 kg/m^2 STANDARD_DEVIATION 3 | 24.50 kg/m^2 STANDARD_DEVIATION 2.97 |
| Duration of diabetes | 0.28 months STANDARD_DEVIATION 1.57 | 0.21 months STANDARD_DEVIATION 1.22 | 0.14 months STANDARD_DEVIATION 0.73 |
| Gender Female | 59 Participants | 119 Participants | 60 Participants |
| Gender Male | 155 Participants | 313 Participants | 158 Participants |
| HbA1c | 10.73 percentage (%) of total haemoglobin STANDARD_DEVIATION 1.5 | 10.82 percentage (%) of total haemoglobin STANDARD_DEVIATION 1.48 | 10.91 percentage (%) of total haemoglobin STANDARD_DEVIATION 1.45 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 214 Participants | 432 Participants | 218 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Weight | 68.2 kg STANDARD_DEVIATION 11 | 68.3 kg STANDARD_DEVIATION 10.9 | 68.3 kg STANDARD_DEVIATION 10.8 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 218 | 0 / 214 |
| serious Total, serious adverse events | 0 / 218 | 1 / 214 |
Outcome results
Primary
Change in Glycosylated Haemoglobin A1c (HbA1c)
Calculated as an estimate of the mean change in HbA1c after 16 weeks of treatment.
Time frame: week -2 (screening), week 16
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Repaglinide + Metformin | Change in Glycosylated Haemoglobin A1c (HbA1c) | -4.450 percentage (%) of total haemoglobin | Standard Error 0.07 |
| Repaglinide | Change in Glycosylated Haemoglobin A1c (HbA1c) | -4.148 percentage (%) of total haemoglobin | Standard Error 0.071 |
Comparison: 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%95% CI: [-0.491, -0.114]ANCOVA
Secondary
Biochemistry: Alanine Aminotransferase (ALAT)
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
Population: Safety analysis set was defined as all randomised and exposed subjects.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Repaglinide + Metformin | Biochemistry: Alanine Aminotransferase (ALAT) | 4 Subjects |
| Repaglinide | Biochemistry: Alanine Aminotransferase (ALAT) | 5 Subjects |
Secondary
Biochemistry: Alanine Aminotransferase (ASAT)
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
Population: Safety analysis set was defined as all randomised and exposed subjects.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Repaglinide + Metformin | Biochemistry: Alanine Aminotransferase (ASAT) | 2 Subjects |
| Repaglinide | Biochemistry: Alanine Aminotransferase (ASAT) | 4 Subjects |
Secondary
Change in 2-hour Postprandial Plasma Glucose
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
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Repaglinide + Metformin | Change in 2-hour Postprandial Plasma Glucose | -7.525 mmol/L | Standard Error 0.237 |
| Repaglinide | Change in 2-hour Postprandial Plasma Glucose | -6.794 mmol/L | Standard Error 0.242 |
Secondary
Change in 2-hour Postprandial Serum C-peptide
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
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Repaglinide + Metformin | Change in 2-hour Postprandial Serum C-peptide | 2.301 ng/ml | Standard Error 0.347 |
| Repaglinide | Change in 2-hour Postprandial Serum C-peptide | 2.081 ng/ml | Standard Error 0.369 |
Secondary
Change in 2-hour Postprandial Serum Insulin
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
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Repaglinide + Metformin | Change in 2-hour Postprandial Serum Insulin | 34.083 mU/L | Standard Error 6.731 |
| Repaglinide | Change in 2-hour Postprandial Serum Insulin | 28.548 mU/L | Standard Error 7.132 |
Secondary
Change in 7-point Plasma Glucose Profile
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
Population: 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 | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Repaglinide + Metformin | Change in 7-point Plasma Glucose Profile | Before breakfast, N=204, 199 | -4.99 mmol/L | Standard Error 0.11 |
| Repaglinide + Metformin | Change in 7-point Plasma Glucose Profile | Bedtime N=195, 188 | -6.93 mmol/L | Standard Error 0.19 |
| Repaglinide + Metformin | Change in 7-point Plasma Glucose Profile | 2 hours after breakfast, N=206, 201 | -7.85 mmol/L | Standard Error 0.23 |
| Repaglinide + Metformin | Change in 7-point Plasma Glucose Profile | 2 hours after dinner N=204, 199 | -7.13 mmol/L | Standard Error 0.21 |
| Repaglinide + Metformin | Change in 7-point Plasma Glucose Profile | Before lunch, N=203, 200 | -6.85 mmol/L | Standard Error 0.18 |
| Repaglinide + Metformin | Change in 7-point Plasma Glucose Profile | Average N=207, 202 | -6.78 mmol/L | Standard Error 0.14 |
| Repaglinide + Metformin | Change in 7-point Plasma Glucose Profile | 2 hours after lunch, N=204, 201 | -8.00 mmol/L | Standard Error 0.21 |
| Repaglinide + Metformin | Change in 7-point Plasma Glucose Profile | Before dinner N=204, 202 | -5.62 mmol/L | Standard Error 0.17 |
| Repaglinide | Change in 7-point Plasma Glucose Profile | Before dinner N=204, 202 | -5.09 mmol/L | Standard Error 0.17 |
| Repaglinide | Change in 7-point Plasma Glucose Profile | 2 hours after dinner N=204, 199 | -5.70 mmol/L | Standard Error 0.22 |
| Repaglinide | Change in 7-point Plasma Glucose Profile | Bedtime N=195, 188 | -5.82 mmol/L | Standard Error 0.19 |
| Repaglinide | Change in 7-point Plasma Glucose Profile | Average N=207, 202 | -5.99 mmol/L | Standard Error 0.14 |
| Repaglinide | Change in 7-point Plasma Glucose Profile | Before breakfast, N=204, 199 | -4.58 mmol/L | Standard Error 0.12 |
| Repaglinide | Change in 7-point Plasma Glucose Profile | 2 hours after breakfast, N=206, 201 | -7.40 mmol/L | Standard Error 0.24 |
| Repaglinide | Change in 7-point Plasma Glucose Profile | Before lunch, N=203, 200 | -6.28 mmol/L | Standard Error 0.18 |
| Repaglinide | Change in 7-point Plasma Glucose Profile | 2 hours after lunch, N=204, 201 | -6.98 mmol/L | Standard Error 0.21 |
Secondary
Change in Blood Pressure
Calculated as the mean change in diastolic and systolic blood pressure after 16 weeks of treatment
Time frame: Week 0, week 16
Population: Safety analysis set was defined as all randomised and exposed subjects.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Repaglinide + Metformin | Change in Blood Pressure | Blood pressure diastolic | -1.0 mmHg | Standard Deviation 8.8 |
| Repaglinide + Metformin | Change in Blood Pressure | Blood pressure systolic | -1.5 mmHg | Standard Deviation 14.3 |
| Repaglinide | Change in Blood Pressure | Blood pressure diastolic | -0.9 mmHg | Standard Deviation 9.5 |
| Repaglinide | Change in Blood Pressure | Blood pressure systolic | -1.4 mmHg | Standard Deviation 14.2 |
Secondary
Change in Fasting Plasma Glucose
Calculated as an estimate of the mean change in fasting plasma glucose after 16 weeks of treatment.
Time frame: week 0, week 16
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Repaglinide + Metformin | Change in Fasting Plasma Glucose | -4.646 mmol/L | Standard Error 0.129 |
| Repaglinide | Change in Fasting Plasma Glucose | -3.982 mmol/L | Standard Error 0.13 |
Secondary
Change in Fasting Serum C-peptide
Calculated as an estimate of the mean change in fasting serum C-peptide after 16 weeks of treatment
Time frame: Week 0, week 16
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Repaglinide + Metformin | Change in Fasting Serum C-peptide | 0.041 ng/ml | Standard Error 0.123 |
| Repaglinide | Change in Fasting Serum C-peptide | 0.405 ng/ml | Standard Error 0.128 |
Secondary
Change in Fasting Serum Insulin
Calculated as an estimate of the mean change in fasting serum insulin after 16 weeks of treatment.
Time frame: Week 0, week 16
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Repaglinide + Metformin | Change in Fasting Serum Insulin | 3.163 mU/L | Standard Error 1.801 |
| Repaglinide | Change in Fasting Serum Insulin | 5.694 mU/L | Standard Error 1.872 |
Secondary
ECG (ElectroCardioGram)
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
Population: Safety analysis set was defined as all randomised and exposed subjects.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Repaglinide + Metformin | ECG (ElectroCardioGram) | 3 Subjects |
| Repaglinide | ECG (ElectroCardioGram) | 2 Subjects |
Secondary
Haematology: Haemoglobin
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
Population: Safety analysis set was defined as all randomised and exposed subjects.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Repaglinide + Metformin | Haematology: Haemoglobin | 1 Subjects |
| Repaglinide | Haematology: Haemoglobin | 0 Subjects |
Secondary
Hypoglycaemic Episodes
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
Population: Safety analysis set was defined as all randomised and exposed subjects.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Repaglinide + Metformin | Hypoglycaemic Episodes | Major | 0 episodes |
| Repaglinide + Metformin | Hypoglycaemic Episodes | Minor | 41 episodes |
| Repaglinide + Metformin | Hypoglycaemic Episodes | Symptoms only | 90 episodes |
| Repaglinide | Hypoglycaemic Episodes | Minor | 16 episodes |
| Repaglinide | Hypoglycaemic Episodes | Symptoms only | 71 episodes |
| Repaglinide | Hypoglycaemic Episodes | Major | 0 episodes |
Secondary
Physical Examinations
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
Population: Safety analysis set was defined as all randomised and exposed subjects.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Repaglinide + Metformin | Physical Examinations | 3 Subjects |
| Repaglinide | Physical Examinations | 0 Subjects |