Diabetes Mellitus, Type 2
Conditions
Brief summary
The purpose of the study was to evaluate the efficacy and safety of LMF237 50/250 mg and 50/500 mg bid in Japanese patients with T2DM inadequately controlled with vildagliptin monotherapy. This study was conducted to support registration of the fixed-dose combination of vildagliptin and metformin for the treatment of T2DM in Japan.
Interventions
DRUGLMF237 50/250 mg
Corresponds to vildagliptin 50 mg twice daily and metformin 250 mg twice daily
DRUGLMF237 50/500 mg
Corresponds to vildagliptin 50 mg twice daily and metformin 500 mg twice daily
DRUGPlacebo
Matching placebo of LMF237 (contained vildagliptin 50 mg as active ingredient) twice daily
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
20 Years to 74 Years
Healthy volunteers
No
Inclusion criteria
* Patients with type 2 diabetes inadequately controlled with diet, exercise and oral anti-diabetic therapy * HbA1c in the range of 7.0-10.0% * Body mass index in the range of 20-35 kg/m\^2
Exclusion criteria
* Type 1 diabetes, monogenic diabetes, diabetes resulting from pancreatic injury, or secondary forms of diabetes * Significant heart diseases Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Glycosylated Hemoglobin (HbA1c) at 14 Weeks Between Treatment Groups | Baseline to 14 weeks | HbA1c was performed on a blood sample obtained and measured by High performance liquid chromatography (HPLC). HPCL was performed at a central laboratory. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in HbA1c at 14 Weeks Within LMF237 Treatment Groups | Baseline to 14 weeks | HbA1c will be performed on a blood sample obtained and measured by HPLC. HPCL was performed at a central laboratory. |
| Percentage of Patients Meeting Responder Rates in HbA1c | Baseline, 14 weeks | Responder rate was analyzed in categories: 1. Endpoint HbA1c ≤ 6.5% 2. Endpoint HbA1c \< 7% 3. Endpoint HbA1c \< 7% in patients with baseline HbA1c ≤ 8% 4. Endpoint HbA1c \< 6.9% 5. HbA1c reduction from baseline at endpoint ≥ 1% 6. HbA1c reduction from baseline at endpoint ≥ 0.5%. Categories 1, 2, and 4 - 'n' includes only patients with baseline HbA1c \> 6.5%, ≥ 7%, ≥ 6.9% and endpoint HbA1c measurement. Category 3, 'n' includes only patients with 7% ≤ baseline HbA1c ≤ 8% and endpoint HbA1c. Category 5 and 6, 'n' indicates number of patients with both baseline and endpoint HbA1c measurements. |
| Change From Baseline in Fasting Plasma Glucose (FPG) at 14 Weeks | Baseline to 14 weeks | FPG was performed on a blood sample obtained and analyzed at a central laboratory. |
| Number of Patients With Adverse Events (Including Hypoglycemia), Serious Adverse Events and Death | 14 weeks | The occurrence of adverse events were sought by non-directive questioning of the patient at each visit. Adverse events are defined as appearance or worsening of any undesirable symptom, sign (including an abnormal laboratory finding), or medical conditions. Serious adverse events are any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgment of investigators represent significant hazards. |
Countries
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| LMF237 50/250 mg Patients took LMF237 50/250 mg twice daily for 14 weeks | 56 |
| LMF237 50/500 mg Patients took LMF237 50/500 mg (with a starting dose of LMF 237 50/250 mg for 2 weeks) twice daily for 14 weeks | 59 |
| Placebo Patients took matching placebo of LMF237 (vildagliptin 50 mg) twice daily for 14 weeks | 56 |
| Total | 171 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Administrative problems | 1 | 0 | 0 |
| Overall Study | Adverse Event | 1 | 3 | 2 |
| Overall Study | Protocol Deviation | 0 | 1 | 0 |
| Overall Study | Unsatisfactory therapeutic effect | 0 | 0 | 3 |
Baseline characteristics
| Characteristic | LMF237 50/250 mg | LMF237 50/500 mg | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 56.6 Years STANDARD_DEVIATION 11.24 | 58.3 Years STANDARD_DEVIATION 10.5 | 56.2 Years STANDARD_DEVIATION 9.75 | 57.0 Years STANDARD_DEVIATION 10.49 |
| Sex: Female, Male Female | 15 Participants | 18 Participants | 16 Participants | 49 Participants |
| Sex: Female, Male Male | 41 Participants | 41 Participants | 40 Participants | 122 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 22 / 115 | 7 / 56 | 15 / 59 | 17 / 56 |
| serious Total, serious adverse events | 1 / 115 | 0 / 56 | 1 / 59 | 2 / 56 |
Outcome results
Primary
Change From Baseline in Glycosylated Hemoglobin (HbA1c) at 14 Weeks Between Treatment Groups
HbA1c was performed on a blood sample obtained and measured by High performance liquid chromatography (HPLC). HPCL was performed at a central laboratory.
Time frame: Baseline to 14 weeks
Population: Full analysis set consisted of all randomized patients who received at least one dose of study medication and had at least one post-randomization efficacy parameter measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pooled LMF237 | Change From Baseline in Glycosylated Hemoglobin (HbA1c) at 14 Weeks Between Treatment Groups | -0.83 percentage of glycosylated haemoglobin | Standard Error 0.06 |
| Placebo | Change From Baseline in Glycosylated Hemoglobin (HbA1c) at 14 Weeks Between Treatment Groups | 0.14 percentage of glycosylated haemoglobin | Standard Error 0.08 |
Secondary
Change From Baseline in Fasting Plasma Glucose (FPG) at 14 Weeks
FPG was performed on a blood sample obtained and analyzed at a central laboratory.
Time frame: Baseline to 14 weeks
Population: FAS consisted of all randomized patients who received at least one dose of study medication and had at least one post-randomization efficacy parameter measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pooled LMF237 | Change From Baseline in Fasting Plasma Glucose (FPG) at 14 Weeks | -13.02 mg/dL | Standard Error 2.83 |
| Placebo | Change From Baseline in Fasting Plasma Glucose (FPG) at 14 Weeks | 16.54 mg/dL | Standard Error 4.06 |
Secondary
Change From Baseline in HbA1c at 14 Weeks Within LMF237 Treatment Groups
HbA1c will be performed on a blood sample obtained and measured by HPLC. HPCL was performed at a central laboratory.
Time frame: Baseline to 14 weeks
Population: Full analysis set consisted of all randomized patients who received at least one dose of study medication and had at least one post-randomization efficacy parameter measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pooled LMF237 | Change From Baseline in HbA1c at 14 Weeks Within LMF237 Treatment Groups | -0.61 percentage of glycosylated haemoglobin | Standard Error 0.06 |
| Placebo | Change From Baseline in HbA1c at 14 Weeks Within LMF237 Treatment Groups | -1.04 percentage of glycosylated haemoglobin | Standard Error 0.06 |
Secondary
Number of Patients With Adverse Events (Including Hypoglycemia), Serious Adverse Events and Death
The occurrence of adverse events were sought by non-directive questioning of the patient at each visit. Adverse events are defined as appearance or worsening of any undesirable symptom, sign (including an abnormal laboratory finding), or medical conditions. Serious adverse events are any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgment of investigators represent significant hazards.
Time frame: 14 weeks
Population: Safety set (SAF): consists of all patients who received at least one dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pooled LMF237 | Number of Patients With Adverse Events (Including Hypoglycemia), Serious Adverse Events and Death | Serious AEs | 0 Patients |
| Pooled LMF237 | Number of Patients With Adverse Events (Including Hypoglycemia), Serious Adverse Events and Death | Any AE (Serious and non-serious) | 25 Patients |
| Pooled LMF237 | Number of Patients With Adverse Events (Including Hypoglycemia), Serious Adverse Events and Death | Death | 0 Patients |
| Placebo | Number of Patients With Adverse Events (Including Hypoglycemia), Serious Adverse Events and Death | Serious AEs | 1 Patients |
| Placebo | Number of Patients With Adverse Events (Including Hypoglycemia), Serious Adverse Events and Death | Any AE (Serious and non-serious) | 25 Patients |
| Placebo | Number of Patients With Adverse Events (Including Hypoglycemia), Serious Adverse Events and Death | Death | 0 Patients |
| Placebo | Number of Patients With Adverse Events (Including Hypoglycemia), Serious Adverse Events and Death | Any AE (Serious and non-serious) | 38 Patients |
| Placebo | Number of Patients With Adverse Events (Including Hypoglycemia), Serious Adverse Events and Death | Death | 0 Patients |
| Placebo | Number of Patients With Adverse Events (Including Hypoglycemia), Serious Adverse Events and Death | Serious AEs | 2 Patients |
Secondary
Percentage of Patients Meeting Responder Rates in HbA1c
Responder rate was analyzed in categories: 1. Endpoint HbA1c ≤ 6.5% 2. Endpoint HbA1c \< 7% 3. Endpoint HbA1c \< 7% in patients with baseline HbA1c ≤ 8% 4. Endpoint HbA1c \< 6.9% 5. HbA1c reduction from baseline at endpoint ≥ 1% 6. HbA1c reduction from baseline at endpoint ≥ 0.5%. Categories 1, 2, and 4 - 'n' includes only patients with baseline HbA1c \> 6.5%, ≥ 7%, ≥ 6.9% and endpoint HbA1c measurement. Category 3, 'n' includes only patients with 7% ≤ baseline HbA1c ≤ 8% and endpoint HbA1c. Category 5 and 6, 'n' indicates number of patients with both baseline and endpoint HbA1c measurements.
Time frame: Baseline, 14 weeks
Population: The full analysis set (FAS) consisted of all randomized patients who received at least one dose of study medication and had at least one post-randomization efficacy parameter measurement.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pooled LMF237 | Percentage of Patients Meeting Responder Rates in HbA1c | HbA1c ≤ 6.5% (n=115, 56) | 27.8 Percentage of patients |
| Pooled LMF237 | Percentage of Patients Meeting Responder Rates in HbA1c | HbA1c < 7.0% (n= 107, 52) | 45.8 Percentage of patients |
| Pooled LMF237 | Percentage of Patients Meeting Responder Rates in HbA1c | HbA1c < 7.0% with baseline HbA1c ≤ 8.0% (n=69,33) | 66.7 Percentage of patients |
| Pooled LMF237 | Percentage of Patients Meeting Responder Rates in HbA1c | HbA1c < 6.9% (n= 111, 54) | 45.0 Percentage of patients |
| Pooled LMF237 | Percentage of Patients Meeting Responder Rates in HbA1c | Reduction of HbA1c ≥ 1% (n= 115, 56) | 36.5 Percentage of patients |
| Pooled LMF237 | Percentage of Patients Meeting Responder Rates in HbA1c | Reduction of HbA1c ≥ 0.5% (n= 115, 56) | 73.9 Percentage of patients |
| Placebo | Percentage of Patients Meeting Responder Rates in HbA1c | Reduction of HbA1c ≥ 1% (n= 115, 56) | 1.8 Percentage of patients |
| Placebo | Percentage of Patients Meeting Responder Rates in HbA1c | HbA1c ≤ 6.5% (n=115, 56) | 0.0 Percentage of patients |
| Placebo | Percentage of Patients Meeting Responder Rates in HbA1c | HbA1c < 6.9% (n= 111, 54) | 9.3 Percentage of patients |
| Placebo | Percentage of Patients Meeting Responder Rates in HbA1c | HbA1c < 7.0% (n= 107, 52) | 13.5 Percentage of patients |
| Placebo | Percentage of Patients Meeting Responder Rates in HbA1c | Reduction of HbA1c ≥ 0.5% (n= 115, 56) | 16.1 Percentage of patients |
| Placebo | Percentage of Patients Meeting Responder Rates in HbA1c | HbA1c < 7.0% with baseline HbA1c ≤ 8.0% (n=69,33) | 18.2 Percentage of patients |