Diabetes Mellitus, Type 2
Conditions
Brief summary
The aim of this study is to investigate the impact of the combination therapy of linagliptin and metformin at submaximal doses in reduction of Glycosylated haemoglobin (HbA1c) and metformin pre-specified gastro-intestinal (GI) side effects in treatment naive patients of with type 2 diabetes mellitus.
Interventions
metformin placebo tablets 500mg
linagliptin placebo tablets 5mg
DRUGmetformin
metformin tablets 500mg
DRUGlinagliptin
linagliptin tablets 5mg
Sponsors
Eli Lilly and Company
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. Diagnosis of Type 2 diabetes mellitus (T2DM) prior to informed consent; 2. Male and female patients on diet and exercise regimen who are drug naive, defined as absence of any oral antidiabetic therapy or insulin for 12 weeks prior to randomization 3. Glycosylated haemoglobin A1c (HbA1c) \>/= 7.0% (53 mmol/mol) to \</= 10.0% (86 mmol/mol) at visit 1 (screening); 4. Age\>/=18 and \</=80 years at visit 1(screening); 5. Body Mass Index (BMI)\</= 45kg/m2 at visit 1 (screening); 6. Signed and dated written informed consent by date of visit 1 in accordance with Good Clinical Practice (GCP) and local legislation
Exclusion criteria
1. Uncontrolled hyperglycaemia with a glucose level \>240 mg/dl (13.3mmol/L) after an overnight fast during screening/placebo run-in and confirmed by a second measurement (Not on the same day); 2. Treatment with any oral antidiabetic drug or insulin within 12 weeks prior to randomization 3. Acute coronary syndrome (non-STEMI, STEMI and unstable angina pectoris),stroke or Transient ischemia attack (TIA) within 3 months prior to informed consent; 4. Indication of liver disease/Impaired hepatic function, defined by serum levels of either Aspartate aminotransferase (ALT or SGPT), alanine aminotransferase (AST or SGOT), or alkaline phosphatase above 3 x upper limit of normal (ULN) as determined at visit 1 and/or run-in phase, 5. Impaired renal function, defined as eGFR\< 60ml/min (moderate or severe renal impairment, modification of diet in renal disease (MDRD) formula) as determined during screening or at run-in phase 6. Bariatric surgery within the past two years and other gastrointestinal surgeries that induced chronic malabsorption 7. Medical history of Cancer (except for basal cell carcinoma) and/or treatment for cancer within the last 5 years 8. Blood dyscrasia or any other disorders causing haemolysis or unstable Red Blood Cell (eg. malaria, babesiosis, haemolytic anemia) 9. Known history of pancreatitis and chronic pancreatitis 10. Contraindications to metformin according to the local label 11. Treatment with anti-obesity drugs 3 months prior to informed consent or any other treatment at the time of screening (i.e. surgery, aggressive diet regimen etc) leading to unstable body weight 12. Current treatment with systemic steroids at time of informed consent or change in dosage of thyroid hormones within 6 weeks prior to informed consent or any other uncontrolled endocrine disorder except T2DM 13. Pre-menopausal women (last menstruation less than 1 year prior to informed consent) who: 1. are nursing or pregnant or 2. are of child-bearing potential and are not practicing an acceptable method of birth control, or do not plan to continue using this method throughout the study and do not agree to submit to periodic pregnancy testing during participation in the trial or who do not agree to continue contraception for at least 30 days after the last dose of study drug. Acceptable methods of birth control include tubal ligation, transdermal patch, intra-uterine devices/systems(IUDs/IUSs), oral, implantable, or injectable contraceptives, complete sexual abstinence (if acceptable by local authorities), double barrier method and vasectomized partner. 14. Alcohol or drug abuse within 3 months prior to informed consent that would interfere with trial participation or any ongoing condition leading to a decreased compliance to study procedures or study drug intake 15. Participation in another trial with application of any investigational drug within 30 days prior to informed consent 16. Any other clinical condition that would jeopardize patients safety while participating in this trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Glycosylated Hemoglobin A1c (HbA1c) After 14 Weeks Treatment | Baseline and 14 weeks | Adjusted mean change in HbA1c from baseline at Week 14 was analysed using an ANCOVA model. The Model included treatment and continuous baseline HbA1c. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Occurence of Metformin Pre-specified Moderate to Severe GI Side Effects Assessed by Investigators During 14 Weeks of Treatment | 14 weeks | Proportion of patients who experienced at least one metformin pre-specified moderate or severe GI side effect during 14 weeks |
| Change From Baseline in Fasting Plasma Glucose (FPG) After 14 Weeks of Treatment | Baseline and 14 weeks | Means are adjusted by treatment, continuous baseline HbA1c and continuous baseline fasting plasma glucose. |
| Metformin Pre-specified GI Symptom Intensity Score Assessed by Investigators During 14 Weeks of Treatment | 14 weeks | Patients could experience multiple events, therefore, multiple answers were possible for each patient. |
| Metformin Pre-specified GI Symptom Intensity Score Assessed by Patients During 14 Weeks of Treatment | 14 weeks | The intensity of the GI side effects was also assessed by the patients using VAS scaled from 0 to 10; higher scores indicate more severe events. Means are adjusted by treatment and continuous baseline HbA1c. |
| Composite Endpoint of Occurrence of Relative Efficacy Response (HbA1c Lowering by at Least 0.8% After 14 Weeks of Treatment) and no Occurrence of Moderate and Severe Metformin Pre-specified GI Side Effects Assessed by Investigators During 14 Weeks | 14 weeks | The proportion of patients who achieved all the targets in a composite endpoint (HbA1c lowered by at least 0.8% after 14 weeks of treatment; no occurrence of pre-specified moderate or severe GI side effects of metformin, as assessed by the investigators during 14 weeks of treatment). |
| Composite Endpoint of Occurrence of Treat to Target Efficacy Response, That is an HbA1c Under Treatment of <7.0% After 14 Weeks of Treatment, on no Occurrence of Moderate or Severe Gastrointestinal (GI) Side Effects During 14 Weeks of Treatment | 14 weeks | The proportion of patients who achieved all the targets in a composite endpoint (HbA1c below 7.0% after 14 weeks of treatment; no occurrence of pre-specified moderate or severe gastrointestinal (GI) side effects of metformin, as assessed by the investigators during 14 weeks of treatment) |
| Composite Endpoint of Occurrence of Treat to Target Efficacy Response, That is an HbA1c Under Treatment of <6.5% After 14 Weeks of Treatment, and no Occurrence of Moderate or Severe Metformin Pre-specified GI Side Effects Assessed by Investigators | 14 weeks | The proportion of patients who achieved all the targets in a composite endpoint (HbA1c below 6.5% after 14 weeks of treatment; no occurrence of pre-specified moderate or severe GI side effects of metformin, as assessed by the investigators during 14 weeks of treatment). |
| Occurrence of Relative Efficacy Response (HbA1c Lowering by at Least 0.5% After 14 Weeks of Treatment) | 14 weeks | The proportion of patients who achieved a relative efficacy response (HbA1c lowering by at least 0.5% after 14 weeks of treatment). |
| Occurrence of Relative Efficacy Response (HbA1c Lowering by at Least 0.8% After 14 Weeks of Treatment) | 14 weeks | The proportion of patients who achieved a relative efficacy response (HbA1c lowering by at least 0.8% after 14 weeks of treatment). |
| Composite Endpoint of Occurence of Relative Efficacy Response (HbA1c Lowering by at Least 0.5% After 14 Weeks of Treatment) and no Occurence of Moderate and Severe Metformin Pre-specified GI Side Effects Assessed by the Investigators During 14 Weeks | 14 weeks | The proportion of patients who achieved all the targets in a composite endpoint (HbA1c lowered by at least 0.5% after 14 weeks of treatment; no occurrence of pre-specified moderate or severe GI side effects of metformin, as assessed by the investigators during 14 weeks of treatment). |
| Change From Baseline in Body Weight by Visit at Week 14 | Baseline and 14 weeks | Means are adjusted by treatment, continuous baseline HbA1c and continuous baseline weight |
| Change From Baseline in HbA1c Over Time | Baseline, 2 weeks and 8 weeks | Means are adjusted by treatment and continuous baseline HbA1c |
Countries
Bangladesh, Belgium, Canada, China, Germany, Guatemala, Hong Kong, India, Lebanon, Mexico, Peru, Philippines, Spain, Taiwan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Lina 5mg + Met qd Patients treated with Linagliptin 5mg in combination with metformin once daily. | 344 |
| Met Bid Patients treated with metformin alone twice daily. | 345 |
| Total | 689 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 3 |
| Overall Study | Lost to Follow-up | 4 | 3 |
| Overall Study | Other | 2 | 4 |
| Overall Study | Protocol Violation | 1 | 2 |
| Overall Study | Withdrawal by Subject | 4 | 2 |
Baseline characteristics
| Characteristic | Lina 5mg + Met qd | Met Bid | Total |
|---|---|---|---|
| Age, Continuous | 53.1 years STANDARD_DEVIATION 10.7 | 52.9 years STANDARD_DEVIATION 10.7 | 53.0 years STANDARD_DEVIATION 10.7 |
| Sex: Female, Male Female | 175 Participants | 187 Participants | 362 Participants |
| Sex: Female, Male Male | 169 Participants | 158 Participants | 327 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 101 / 344 | 121 / 345 |
| serious Total, serious adverse events | 2 / 344 | 7 / 345 |
Outcome results
Primary
Change From Baseline in Glycosylated Hemoglobin A1c (HbA1c) After 14 Weeks Treatment
Adjusted mean change in HbA1c from baseline at Week 14 was analysed using an ANCOVA model. The Model included treatment and continuous baseline HbA1c.
Time frame: Baseline and 14 weeks
Population: FAS1000mg with last observation carried forward (LOCF): all patients randomised and treated who had a baseline at least 1 on-treatment HbA1c value and who tolerated a daily metformin dose of at least 1000 mg at the end of the titration phase.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lina 5mg + Met qd | Change From Baseline in Glycosylated Hemoglobin A1c (HbA1c) After 14 Weeks Treatment | -0.99 percent | Standard Error 0.05 |
| Met Bid | Change From Baseline in Glycosylated Hemoglobin A1c (HbA1c) After 14 Weeks Treatment | -0.98 percent | Standard Error 0.04 |
p-value: <0.000195% CI: [-0.13, 0.12]ANCOVA
p-value: 0.892495% CI: [-0.13, 0.12]ANCOVA
Secondary
Change From Baseline in Body Weight by Visit at Week 14
Means are adjusted by treatment, continuous baseline HbA1c and continuous baseline weight
Time frame: Baseline and 14 weeks
Population: FAS1000 having values for weight at baseline and week 14.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lina 5mg + Met qd | Change From Baseline in Body Weight by Visit at Week 14 | -0.44 kg | Standard Error 0.14 |
| Met Bid | Change From Baseline in Body Weight by Visit at Week 14 | -1.05 kg | Standard Error 0.13 |
p-value: 0.001195% CI: [0.25, 0.98]ANCOVA
Secondary
Change From Baseline in Fasting Plasma Glucose (FPG) After 14 Weeks of Treatment
Means are adjusted by treatment, continuous baseline HbA1c and continuous baseline fasting plasma glucose.
Time frame: Baseline and 14 weeks
Population: Patients from FAS1000 with LOCF
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lina 5mg + Met qd | Change From Baseline in Fasting Plasma Glucose (FPG) After 14 Weeks of Treatment | -24.5 mg/dL | Standard Error 1.5 |
| Met Bid | Change From Baseline in Fasting Plasma Glucose (FPG) After 14 Weeks of Treatment | -26.6 mg/dL | Standard Error 1.4 |
p-value: 0.335295% CI: [-2.1, 6.1]ANCOVA
Secondary
Change From Baseline in HbA1c Over Time
Means are adjusted by treatment and continuous baseline HbA1c
Time frame: Baseline, 2 weeks and 8 weeks
Population: Patients from FAS1000 (LOCF)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lina 5mg + Met qd | Change From Baseline in HbA1c Over Time | At week 2 | -0.28 percent | Standard Error 0.02 |
| Lina 5mg + Met qd | Change From Baseline in HbA1c Over Time | At week 8 | -0.84 percent | Standard Error 0.04 |
| Met Bid | Change From Baseline in HbA1c Over Time | At week 2 | -0.25 percent | Standard Error 0.02 |
| Met Bid | Change From Baseline in HbA1c Over Time | At week 8 | -0.78 percent | Standard Error 0.04 |
Secondary
Composite Endpoint of Occurence of Relative Efficacy Response (HbA1c Lowering by at Least 0.5% After 14 Weeks of Treatment) and no Occurence of Moderate and Severe Metformin Pre-specified GI Side Effects Assessed by the Investigators During 14 Weeks
The proportion of patients who achieved all the targets in a composite endpoint (HbA1c lowered by at least 0.5% after 14 weeks of treatment; no occurrence of pre-specified moderate or severe GI side effects of metformin, as assessed by the investigators during 14 weeks of treatment).
Time frame: 14 weeks
Population: Patients from FAS1000 (NCF)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lina 5mg + Met qd | Composite Endpoint of Occurence of Relative Efficacy Response (HbA1c Lowering by at Least 0.5% After 14 Weeks of Treatment) and no Occurence of Moderate and Severe Metformin Pre-specified GI Side Effects Assessed by the Investigators During 14 Weeks | 194 participants |
| Met Bid | Composite Endpoint of Occurence of Relative Efficacy Response (HbA1c Lowering by at Least 0.5% After 14 Weeks of Treatment) and no Occurence of Moderate and Severe Metformin Pre-specified GI Side Effects Assessed by the Investigators During 14 Weeks | 236 participants |
p-value: 0.281695% CI: [0.594, 1.163]Regression, Logistic
Secondary
Composite Endpoint of Occurrence of Relative Efficacy Response (HbA1c Lowering by at Least 0.8% After 14 Weeks of Treatment) and no Occurrence of Moderate and Severe Metformin Pre-specified GI Side Effects Assessed by Investigators During 14 Weeks
The proportion of patients who achieved all the targets in a composite endpoint (HbA1c lowered by at least 0.8% after 14 weeks of treatment; no occurrence of pre-specified moderate or severe GI side effects of metformin, as assessed by the investigators during 14 weeks of treatment).
Time frame: 14 weeks
Population: Patients from FAS1000 (NCF)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lina 5mg + Met qd | Composite Endpoint of Occurrence of Relative Efficacy Response (HbA1c Lowering by at Least 0.8% After 14 Weeks of Treatment) and no Occurrence of Moderate and Severe Metformin Pre-specified GI Side Effects Assessed by Investigators During 14 Weeks | 149 participants |
| Met Bid | Composite Endpoint of Occurrence of Relative Efficacy Response (HbA1c Lowering by at Least 0.8% After 14 Weeks of Treatment) and no Occurrence of Moderate and Severe Metformin Pre-specified GI Side Effects Assessed by Investigators During 14 Weeks | 175 participants |
p-value: 0.768295% CI: [0.681, 1.328]Regression, Logistic
Secondary
Composite Endpoint of Occurrence of Treat to Target Efficacy Response, That is an HbA1c Under Treatment of <6.5% After 14 Weeks of Treatment, and no Occurrence of Moderate or Severe Metformin Pre-specified GI Side Effects Assessed by Investigators
The proportion of patients who achieved all the targets in a composite endpoint (HbA1c below 6.5% after 14 weeks of treatment; no occurrence of pre-specified moderate or severe GI side effects of metformin, as assessed by the investigators during 14 weeks of treatment).
Time frame: 14 weeks
Population: Patients from FAS1000 (NCF) having a baseline HbA1c\>=6.5%.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lina 5mg + Met qd | Composite Endpoint of Occurrence of Treat to Target Efficacy Response, That is an HbA1c Under Treatment of <6.5% After 14 Weeks of Treatment, and no Occurrence of Moderate or Severe Metformin Pre-specified GI Side Effects Assessed by Investigators | 83 participants |
| Met Bid | Composite Endpoint of Occurrence of Treat to Target Efficacy Response, That is an HbA1c Under Treatment of <6.5% After 14 Weeks of Treatment, and no Occurrence of Moderate or Severe Metformin Pre-specified GI Side Effects Assessed by Investigators | 95 participants |
p-value: 0.988695% CI: [0.689, 1.445]Regression, Logistic
Secondary
Composite Endpoint of Occurrence of Treat to Target Efficacy Response, That is an HbA1c Under Treatment of <7.0% After 14 Weeks of Treatment, on no Occurrence of Moderate or Severe Gastrointestinal (GI) Side Effects During 14 Weeks of Treatment
The proportion of patients who achieved all the targets in a composite endpoint (HbA1c below 7.0% after 14 weeks of treatment; no occurrence of pre-specified moderate or severe gastrointestinal (GI) side effects of metformin, as assessed by the investigators during 14 weeks of treatment)
Time frame: 14 weeks
Population: Patients from FAS1000 with non-completer considered as failure (NCF) having a baseline HbA1c\>=7.0%.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lina 5mg + Met qd | Composite Endpoint of Occurrence of Treat to Target Efficacy Response, That is an HbA1c Under Treatment of <7.0% After 14 Weeks of Treatment, on no Occurrence of Moderate or Severe Gastrointestinal (GI) Side Effects During 14 Weeks of Treatment | 119 participants |
| Met Bid | Composite Endpoint of Occurrence of Treat to Target Efficacy Response, That is an HbA1c Under Treatment of <7.0% After 14 Weeks of Treatment, on no Occurrence of Moderate or Severe Gastrointestinal (GI) Side Effects During 14 Weeks of Treatment | 148 participants |
p-value: 0.820195% CI: [0.672, 1.37]Regression, Logistic
Secondary
Metformin Pre-specified GI Symptom Intensity Score Assessed by Investigators During 14 Weeks of Treatment
Patients could experience multiple events, therefore, multiple answers were possible for each patient.
Time frame: 14 weeks
Population: Patients from FAS1000 and having GI adverse events which were assessed for severity by the investigator.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lina 5mg + Met qd | Metformin Pre-specified GI Symptom Intensity Score Assessed by Investigators During 14 Weeks of Treatment | Mild | 114 events |
| Lina 5mg + Met qd | Metformin Pre-specified GI Symptom Intensity Score Assessed by Investigators During 14 Weeks of Treatment | Moderate | 37 events |
| Lina 5mg + Met qd | Metformin Pre-specified GI Symptom Intensity Score Assessed by Investigators During 14 Weeks of Treatment | Severe | 6 events |
| Met Bid | Metformin Pre-specified GI Symptom Intensity Score Assessed by Investigators During 14 Weeks of Treatment | Mild | 153 events |
| Met Bid | Metformin Pre-specified GI Symptom Intensity Score Assessed by Investigators During 14 Weeks of Treatment | Moderate | 65 events |
| Met Bid | Metformin Pre-specified GI Symptom Intensity Score Assessed by Investigators During 14 Weeks of Treatment | Severe | 1 events |
p-value: 0.0308Fisher Exact
Secondary
Metformin Pre-specified GI Symptom Intensity Score Assessed by Patients During 14 Weeks of Treatment
The intensity of the GI side effects was also assessed by the patients using VAS scaled from 0 to 10; higher scores indicate more severe events. Means are adjusted by treatment and continuous baseline HbA1c.
Time frame: 14 weeks
Population: Patients from the FAS1000 using original results (OR) and having GI adverse events which were assessed for severity by the patient.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lina 5mg + Met qd | Metformin Pre-specified GI Symptom Intensity Score Assessed by Patients During 14 Weeks of Treatment | 4.9 units on a scale | Standard Error 0.2 |
| Met Bid | Metformin Pre-specified GI Symptom Intensity Score Assessed by Patients During 14 Weeks of Treatment | 4.4 units on a scale | Standard Error 0.2 |
p-value: 0.054595% CI: [0, 1]ANCOVA
Secondary
Occurence of Metformin Pre-specified Moderate to Severe GI Side Effects Assessed by Investigators During 14 Weeks of Treatment
Proportion of patients who experienced at least one metformin pre-specified moderate or severe GI side effect during 14 weeks
Time frame: 14 weeks
Population: Patients from FAS1000
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lina 5mg + Met qd | Occurence of Metformin Pre-specified Moderate to Severe GI Side Effects Assessed by Investigators During 14 Weeks of Treatment | 25 participants |
| Met Bid | Occurence of Metformin Pre-specified Moderate to Severe GI Side Effects Assessed by Investigators During 14 Weeks of Treatment | 28 participants |
p-value: 0.939795% CI: [0.582, 1.796]Regression, Logistic
Secondary
Occurrence of Relative Efficacy Response (HbA1c Lowering by at Least 0.5% After 14 Weeks of Treatment)
The proportion of patients who achieved a relative efficacy response (HbA1c lowering by at least 0.5% after 14 weeks of treatment).
Time frame: 14 weeks
Population: Patients from FAS1000 (NCF)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lina 5mg + Met qd | Occurrence of Relative Efficacy Response (HbA1c Lowering by at Least 0.5% After 14 Weeks of Treatment) | 211 participants |
| Met Bid | Occurrence of Relative Efficacy Response (HbA1c Lowering by at Least 0.5% After 14 Weeks of Treatment) | 257 participants |
p-value: 0.210895% CI: [0.558, 1.137]Regression, Logistic
Secondary
Occurrence of Relative Efficacy Response (HbA1c Lowering by at Least 0.8% After 14 Weeks of Treatment)
The proportion of patients who achieved a relative efficacy response (HbA1c lowering by at least 0.8% after 14 weeks of treatment).
Time frame: 14 weeks
Population: Patients from the FAS1000 (NCF)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lina 5mg + Met qd | Occurrence of Relative Efficacy Response (HbA1c Lowering by at Least 0.8% After 14 Weeks of Treatment) | 162 participants |
| Met Bid | Occurrence of Relative Efficacy Response (HbA1c Lowering by at Least 0.8% After 14 Weeks of Treatment) | 187 participants |
p-value: 0.997295% CI: [0.712, 1.402]Regression, Logistic