Diabetes Mellitus, Type 2
Conditions
Brief summary
The primary objective is to demonstrate superior glycaemic control (HbA1c reduction) after 30 weeks of linagliptin/pioglitazone (5/15, 5/30 and 5/45 mg) versus the respective individual monotherapies of pioglitazone (15 mg, 30 mg, or 45 mg, administered orally once daily), and linagliptin (5 mg, administered orally once daily). In addition, durability of treatment effect and safety under chronic treatment conditions will be investigated.
Interventions
Pioglitazone Capsules 15 mg once daily for 30 weeks followed by Pioglitazone Capsules 30 mg once daily for up to 54 weeks
Pioglitazone Capsules 30 mg once daily for 6 weeks followed by Pioglitazone Capsules 45 mg once daily for up to 78 weeks
Pioglitazone Capsules 30 mg once daily for up to 84 weeks
DRUGLinagliptin 5mg / Pioglitazone 45 mg FDC
Linagliptin 5mg low dose / Pioglitazone 30 mg Tablets once daily for 6 weeks followed by Linagliptin 5mg low dose / Pioglitazone 45 mg FDC Tablets once daily for up to 78 weeks
DRUGLinagliptin 5mg / Pioglitazone 30 mg FDC
Linagliptin 5mg low dose / Pioglitazone 30 mg FDC Tablets once daily for up to 84 weeks
DRUGLinagliptin 5mg
Linagliptin 5mg Tablets low dose once daily for 30 weeks followed by Linagliptin 5mg low dose / Pioglitazone 30 mg FDC Tablets once daily for up to 54 weeks
DRUGLinagliptin 5mg / Pioglitazone 15 mg FDC
Linagliptin 5mg low dose / Pioglitazone 15 mg FDC Tablets once daily for 30 weeks followed by Linagliptin 5mg low dose / Pioglitazone 30 mg FDC Tablets once daily for up to 54 weeks
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 prior to informed consent 2. Male and female patients with insufficient glycaemic control (HbA1c \>= 7.0 to \<= 10.5% at Visit 2) on diet and exercise alone, without oral antidiabetic drug therapy within 10 weeks prior to start of the run-in period (date of Visit 2) 3. Age \>= 18 and \<= 80 years at start date of Visit 1 (Screening) 4. BMI \<= 45 kg/m2 (Body Mass Index) at start date of Visit 1 (Screening) 5. Signed and dated written informed consent by start date of Visit 1 in accordance with GCP and local legislation
Exclusion criteria
1. Uncontrolled hyperglycaemia with a confirmed glucose level \> 240 mg/dl (\> 13.3 mmol/l) after an overnight fast during screening or placebo run-in period (cf. Section 3.3.4.1) 2. Myocardial infarction within 6 months, stroke or TIA within 3 months prior to informed consent 3. Clinical evidence of active liver disease (e.g. jaundice) or the ALT level \> 2.5 times the upper limit of normal (according to pioglitazone label) 4. Bariatric surgery, performed within the past 2 years prior to informed consent or planned at the time of informed consent 5. Gastrointestinal surgeries prior to informed consent that induce chronic malabsorption 6. Known hypersensitivity or allergy to the investigational products (linagliptin and/or pioglitazone) or their excipients (including matching placebos) 7. Contraindications to pioglitazone as defined in the local prescribing information (SPC), particularly : * Diagnose of heart failure or history of heart failure * Haemodialysis patients, due to limited experience with pioglitazone 8. Treatment with gemfibrozil, montelukast, trimethoprim, or rifampicin - according to pioglitazone label and respective restrictions in Section 4.2.2 9. Treatment with rosiglitazone, pioglitazone, GLP-1 analogues, or insulin within 3 months prior to informed consent 10. Treatment with anti-obesity drugs (e.g. sibutramine, orlistat) 3 months prior to informed consent 11. Alcohol or drug abuse within the 3 months prior to informed consent or history of alcoholism 12. Current treatment with systemic corticosteroids at time of informed consent or change in dosage of thyroid hormones within 6 weeks prior to informed consent 13. Participation in another trial with an investigational drug within 30 days prior to informed consent 14. Any other clinical condition as judged by the investigator that would not allow the safe completion of the protocol, e.g. inability of patients to comply with study procedures 15. Pre-menopausal women (last menstruation \<= 1 year prior to informed consent) who: * are nursing or pregnant or * are of child-bearing potential (i.e. not permanently sterilised) and are not practicing a highly effective 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. A highly effective method of birth control is defined - according to the Note for Guidance on non-clinical safety studies for the conduct of human trials for pharmaceuticals (CPMP/ICH/286/95, modification) - as those which result in a low failure rate (i. e. less than 1% per year) when used consistently and correctly such as implants, injectables, combined oral contraceptives, hormonal intrauterine devices/systems (IUDs/IUSs), sexual abstinence or vasectomised partner 16. Symptomatic gallbladder disease in the last six months 17. Medical history of pancreatitis. 18. Patients with urinary bladder cancer or a history of urinary bladder cancer or uninvestigated macroscopic haematuria 19. Any other contraindication or restriction for use of pioglitazone in accordance with the local prescribing information for pioglitazone.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in HbA1c After 30 Weeks of Treatment. | Baseline and 30 weeks | HbA1c is measured as a percentage. The change from baseline is the Week 30 HbA1c minus the baseline HbA1c. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Occurrence of Cumulative Treat to Target Efficacy Response, of HbA1c Under Treatment of < 6.5% After 30 Weeks of Treatment | Baseline and 30 weeks | Glycosylated hemoglobin is reported as a percentage of the total hemoglobin. |
| Occurrence of Relative Efficacy Response (HbA1c Lowering by at Least 0.5% After 30 Weeks of Treatment) | Baseline and 30 weeks | Glycosylated hemoglobin is reported as a percentage of the total hemoglobin. |
| HbA1c Change From Baseline by Visit Over Time | Baseline, week 6, week 12, week 18, week 24, week 30 | HbA1c is measured as a percentage. The change from baseline is the HbA1c over time minus the baseline HbA1c. The model includes fixed effects for treatment, continuous baseline HbA1c, prior andi-diabetic medication, country, visit and treatment. by visit interaction. |
| Fasting Plasma Glucose (FPG) Change From Baseline After 30 Weeks of Treatment | Baseline and 30 weeks | The change from baseline is the FPG after 30 weeks minus the baseline FPG. |
| Occurrence of Cumulative Treat to Target Efficacy Response, of HbA1c Under Treatment of < 7.0% After 30 Weeks of Treatment | Baseline and 30 weeks | Glycosylated hemoglobin is reported as a percentage of the total hemoglobin. |
| Two-hour Postprandial Glucose (2hPPG) Change From Baseline at Week 30 by Meal Tolerance Test (MTT) | Baseline and 30 weeks | The change from baseline is the 2hPPG after 30 weeks minus the baseline 2hPPG. |
| Time to First Use of Rescue Therapy | 30 weeks | Proportion of patients at 30 weeks with rescue therapy using Kaplan-Meier analysis. |
| Incidence of Rescue Therapy During the First 30 Weeks of Treatment | 30 weeks | Rescue therapy was defined to include any new antidiabetic medication taken for hyperglycemia and introduced on or after the start date of study treatment and before the end date of study treatment. |
| Fasting Plasma Glucose (FPG) Change From Baseline by Visit Over Time | Baseline, week 6, week 12, week 18, week 24, week 30 | The change from baseline is the FPG over time minus the baseline FPG. Model includes fixed effects for treatment, continuous baseline FPG, continuous baseline HbA1c, prior anti-diabetic medication, country, visit and treatment by visit interaction |
Countries
Estonia, Germany, Latvia, Spain, United Kingdom, United States
Participant flow
Recruitment details
After Amendment #5, patients were considered COMPLETED at the end of Part A (30 weeks) or after their next Part B visit (up to 54 weeks) if already in Part B. Before Amendment #5, all patients were considered COMPLETED at the end of Part A + Part B (84 weeks).
Participants by arm
| Arm | Count |
|---|---|
| Pio15/Pio30 Participants treated with pioglitazone 15mg for 30 weeks followed by pioglitazone 30mg for up to 54 weeks. | 124 |
| Pio30/Pio30 Participants treated with pioglitazone 30mg for 30 weeks followed by pioglitazone 30mg for up to 54 weeks. | 134 |
| Pio45/Pio45 Participants treated with pioglitazone 30 mg for 6 weeks and then were titrated up to pioglitazone 45mg for 24 weeks followed by pioglitazone 45mg for up to 54 weeks. | 134 |
| Lina5/Lina5 Participants treated with linagliptin 5mg + pioglitazone 15mg fixed dose combination (FDC) for 30 weeks followed by linagliptin 5mg + pioglitazone 30mg FDC for up to 54 weeks. | 130 |
| Lina5Pio15/Lina5Pio30 Participants treated with linagliptin 5mg + pioglitazone 15mg fixed dose combination (FDC) for 30 weeks followed by a blinded trial period on linagliptin 5mg + pioglitazone 30mg FDC | 120 |
| Lina5Pio30/Lina5Pio30 Participants treated with linagliptin 5mg + pioglitazone 30mg fixed dose combination (FDC) for 30 weeks followed by linagliptin 5mg + pioglitazone 30mg FDC for up to 54 weeks. | 125 |
| Lina5Pio45/Lina5Pio45 Participants treated with linagliptin 5mg + pioglitazone 30mg fixed dose combination (FDC) for 6 weeks and linagliptin 5mg + pioglitazone 45mg FDC for 24 weeks followed by linagliptin 5mg + pioglitazone 45mg FDC for up to 54 weeks. | 126 |
| Total | 893 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 6 | 8 | 5 | 5 | 10 | 10 | 6 |
| Overall Study | Lack of Efficacy | 3 | 2 | 1 | 2 | 1 | 2 | 0 |
| Overall Study | Lost to Follow-up | 7 | 3 | 4 | 3 | 2 | 6 | 5 |
| Overall Study | Protocol Violation | 5 | 2 | 4 | 0 | 4 | 3 | 3 |
| Overall Study | Reasons other than stated above | 15 | 11 | 17 | 12 | 12 | 15 | 13 |
| Overall Study | Withdrawal by Subject | 9 | 13 | 10 | 8 | 7 | 9 | 10 |
Baseline characteristics
| Characteristic | Pio15/Pio30 | Pio30/Pio30 | Pio45/Pio45 | Lina5/Lina5 | Lina5Pio15/Lina5Pio30 | Lina5Pio30/Lina5Pio30 | Lina5Pio45/Lina5Pio45 | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 56.4 years STANDARD_DEVIATION 10.4 | 57.2 years STANDARD_DEVIATION 11.1 | 56.5 years STANDARD_DEVIATION 11.1 | 56.3 years STANDARD_DEVIATION 10.1 | 57.1 years STANDARD_DEVIATION 10.2 | 56.4 years STANDARD_DEVIATION 10 | 60.1 years STANDARD_DEVIATION 10.2 | 57.1 years STANDARD_DEVIATION 10.5 |
| Baseline fasting plasma glucose (FPG) | 171.3 mg/dL STANDARD_DEVIATION 39.3 | 165.8 mg/dL STANDARD_DEVIATION 40 | 167.5 mg/dL STANDARD_DEVIATION 37.9 | 161.4 mg/dL STANDARD_DEVIATION 38.1 | 167.3 mg/dL STANDARD_DEVIATION 39.5 | 168.8 mg/dL STANDARD_DEVIATION 46.8 | 162.3 mg/dL STANDARD_DEVIATION 36.8 | 166.3 mg/dL STANDARD_DEVIATION 39.9 |
| Baseline HbA1c | 8.33 percent STANDARD_DEVIATION 0.93 | 7.99 percent STANDARD_DEVIATION 0.85 | 8.12 percent STANDARD_DEVIATION 0.87 | 8.01 percent STANDARD_DEVIATION 0.88 | 8.13 percent STANDARD_DEVIATION 0.94 | 8.17 percent STANDARD_DEVIATION 1.07 | 8.01 percent STANDARD_DEVIATION 0.81 | 8.11 percent STANDARD_DEVIATION 0.91 |
| Sex: Female, Male Female | 57 Participants | 64 Participants | 66 Participants | 51 Participants | 54 Participants | 61 Participants | 57 Participants | 410 Participants |
| Sex: Female, Male Male | 67 Participants | 70 Participants | 68 Participants | 79 Participants | 66 Participants | 64 Participants | 69 Participants | 483 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 57 / 131 | 55 / 140 | 66 / 138 | 57 / 135 | 52 / 126 | 58 / 133 | 56 / 133 |
| serious Total, serious adverse events | 9 / 131 | 9 / 140 | 5 / 138 | 9 / 135 | 9 / 126 | 15 / 133 | 10 / 133 |
Outcome results
Primary
Change From Baseline in HbA1c After 30 Weeks of Treatment.
HbA1c is measured as a percentage. The change from baseline is the Week 30 HbA1c minus the baseline HbA1c.
Time frame: Baseline and 30 weeks
Population: Patients from Full Analysis Set (FAS) with last observation carried forward (LOCF) used to handle missing values at Week 30. FAS is the patient set which includes all patients who were documented to have taken at least one dose of treatment and who had a baseline HbA1c value at at least one on-treatment HbA1c.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pio15 | Change From Baseline in HbA1c After 30 Weeks of Treatment. | -0.66 percent | Standard Error 0.09 |
| Pio30 | Change From Baseline in HbA1c After 30 Weeks of Treatment. | -0.69 percent | Standard Error 0.09 |
| Pio45 | Change From Baseline in HbA1c After 30 Weeks of Treatment. | -0.87 percent | Standard Error 0.09 |
| Lina5 | Change From Baseline in HbA1c After 30 Weeks of Treatment. | -0.39 percent | Standard Error 0.09 |
| Lina5Pio15 | Change From Baseline in HbA1c After 30 Weeks of Treatment. | -0.83 percent | Standard Error 0.09 |
| Lina5Pio30 | Change From Baseline in HbA1c After 30 Weeks of Treatment. | -1.06 percent | Standard Error 0.09 |
| Lina5Pio45 | Change From Baseline in HbA1c After 30 Weeks of Treatment. | -1.28 percent | Standard Error 0.09 |
Comparison: Treatment comparisons are for fixed dose combination versus monotherapy.p-value: 0.157195% CI: [-0.41, 0.07]ANCOVA
Comparison: Treatment comparisons are for fixed dose combination versus monotherapy.p-value: 0.001695% CI: [-0.6, -0.14]ANCOVA
Comparison: Treatment comparisons are for fixed dose combination versus monotherapy.p-value: 0.000695% CI: [-0.64, -0.18]ANCOVA
Comparison: Treatment comparisons are for fixed dose combination versus monotherapy.p-value: 0.000395% CI: [-0.67, -0.2]ANCOVA
Comparison: Treatment comparisons are for fixed dose combination versus monotherapy.p-value: <0.000195% CI: [-0.91, -0.44]ANCOVA
Comparison: Treatment comparisons are for fixed dose combination versus monotherapy.p-value: <0.000195% CI: [-1.12, -0.66]ANCOVA
Secondary
Fasting Plasma Glucose (FPG) Change From Baseline After 30 Weeks of Treatment
The change from baseline is the FPG after 30 weeks minus the baseline FPG.
Time frame: Baseline and 30 weeks
Population: Patients from Full Analysis Set (FAS) with a value for FPG at baseline and on-treatment. Last observation carried forward (LOCF) used to handle missing values at Week 30.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pio15 | Fasting Plasma Glucose (FPG) Change From Baseline After 30 Weeks of Treatment | -15.16 mg/dL | Standard Error 3.49 |
| Pio30 | Fasting Plasma Glucose (FPG) Change From Baseline After 30 Weeks of Treatment | -25.49 mg/dL | Standard Error 3.28 |
| Pio45 | Fasting Plasma Glucose (FPG) Change From Baseline After 30 Weeks of Treatment | -28.69 mg/dL | Standard Error 3.29 |
| Lina5 | Fasting Plasma Glucose (FPG) Change From Baseline After 30 Weeks of Treatment | -1.46 mg/dL | Standard Error 3.35 |
| Lina5Pio15 | Fasting Plasma Glucose (FPG) Change From Baseline After 30 Weeks of Treatment | -18.84 mg/dL | Standard Error 3.47 |
| Lina5Pio30 | Fasting Plasma Glucose (FPG) Change From Baseline After 30 Weeks of Treatment | -27.33 mg/dL | Standard Error 3.46 |
| Lina5Pio45 | Fasting Plasma Glucose (FPG) Change From Baseline After 30 Weeks of Treatment | -35.19 mg/dL | Standard Error 3.4 |
Comparison: Treatment comparisons are for fixed dose combination versus monotherapy.p-value: 0.427595% CI: [-12.77, 5.42]ANCOVA
Comparison: Treatment comparisons are for fixed dose combination versus monotherapy.p-value: 0.683995% CI: [-10.69, 7.02]ANCOVA
Comparison: Treatment comparisons are for fixed dose combination versus monotherapy.p-value: 0.146695% CI: [-15.29, 2.28]ANCOVA
Comparison: Treatment comparisons are for fixed dose combination versus monotherapy.p-value: 0.000295% CI: [-26.35, -8.41]ANCOVA
Comparison: Treatment comparisons are for fixed dose combination versus monotherapy.p-value: <0.000195% CI: [-34.77, -16.98]ANCOVA
Comparison: Treatment comparisons are for fixed dose combination versus monotherapy.p-value: <0.000195% CI: [-42.57, -24.89]ANCOVA
Secondary
Fasting Plasma Glucose (FPG) Change From Baseline by Visit Over Time
The change from baseline is the FPG over time minus the baseline FPG. Model includes fixed effects for treatment, continuous baseline FPG, continuous baseline HbA1c, prior anti-diabetic medication, country, visit and treatment by visit interaction
Time frame: Baseline, week 6, week 12, week 18, week 24, week 30
Population: FAS (observed cases)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pio15 | Fasting Plasma Glucose (FPG) Change From Baseline by Visit Over Time | Change at week 18 (N=100,122,121,111,104,103,114) | -16.68 mg/dL | Standard Error 3.29 |
| Pio15 | Fasting Plasma Glucose (FPG) Change From Baseline by Visit Over Time | Change at week 30 (N=76,91,89,79,82,87,98) | -17.66 mg/dL | Standard Error 3.35 |
| Pio15 | Fasting Plasma Glucose (FPG) Change From Baseline by Visit Over Time | Change at week 12 (N=111,124,126,122,108,114,118) | -10.63 mg/dL | Standard Error 3.24 |
| Pio15 | Fasting Plasma Glucose (FPG) Change From Baseline by Visit Over Time | Change at week 6 (N=118,132,133,130,119,122,124) | -14.43 mg/dL | Standard Error 2.99 |
| Pio15 | Fasting Plasma Glucose (FPG) Change From Baseline by Visit Over Time | Change at week 24 (N=90,108,108,96,93,93,108) | -16.25 mg/dL | Standard Error 3.25 |
| Pio30 | Fasting Plasma Glucose (FPG) Change From Baseline by Visit Over Time | Change at week 6 (N=118,132,133,130,119,122,124) | -16.38 mg/dL | Standard Error 2.8 |
| Pio30 | Fasting Plasma Glucose (FPG) Change From Baseline by Visit Over Time | Change at week 24 (N=90,108,108,96,93,93,108) | -21.57 mg/dL | Standard Error 2.99 |
| Pio30 | Fasting Plasma Glucose (FPG) Change From Baseline by Visit Over Time | Change at week 30 (N=76,91,89,79,82,87,98) | -26.09 mg/dL | Standard Error 3.08 |
| Pio30 | Fasting Plasma Glucose (FPG) Change From Baseline by Visit Over Time | Change at week 12 (N=111,124,126,122,108,114,118) | -21.36 mg/dL | Standard Error 3.04 |
| Pio30 | Fasting Plasma Glucose (FPG) Change From Baseline by Visit Over Time | Change at week 18 (N=100,122,121,111,104,103,114) | -20.69 mg/dL | Standard Error 3.02 |
| Pio45 | Fasting Plasma Glucose (FPG) Change From Baseline by Visit Over Time | Change at week 30 (N=76,91,89,79,82,87,98) | -31.76 mg/dL | Standard Error 3.11 |
| Pio45 | Fasting Plasma Glucose (FPG) Change From Baseline by Visit Over Time | Change at week 12 (N=111,124,126,122,108,114,118) | -25.30 mg/dL | Standard Error 3.03 |
| Pio45 | Fasting Plasma Glucose (FPG) Change From Baseline by Visit Over Time | Change at week 24 (N=90,108,108,96,93,93,108) | -27.67 mg/dL | Standard Error 3 |
| Pio45 | Fasting Plasma Glucose (FPG) Change From Baseline by Visit Over Time | Change at week 6 (N=118,132,133,130,119,122,124) | -15.72 mg/dL | Standard Error 2.81 |
| Pio45 | Fasting Plasma Glucose (FPG) Change From Baseline by Visit Over Time | Change at week 18 (N=100,122,121,111,104,103,114) | -28.68 mg/dL | Standard Error 3.03 |
| Lina5 | Fasting Plasma Glucose (FPG) Change From Baseline by Visit Over Time | Change at week 6 (N=118,132,133,130,119,122,124) | -4.25 mg/dL | Standard Error 2.84 |
| Lina5 | Fasting Plasma Glucose (FPG) Change From Baseline by Visit Over Time | Change at week 12 (N=111,124,126,122,108,114,118) | -7.43 mg/dL | Standard Error 3.08 |
| Lina5 | Fasting Plasma Glucose (FPG) Change From Baseline by Visit Over Time | Change at week 18 (N=100,122,121,111,104,103,114) | -7.06 mg/dL | Standard Error 3.13 |
| Lina5 | Fasting Plasma Glucose (FPG) Change From Baseline by Visit Over Time | Change at week 24 (N=90,108,108,96,93,93,108) | -4.60 mg/dL | Standard Error 3.13 |
| Lina5 | Fasting Plasma Glucose (FPG) Change From Baseline by Visit Over Time | Change at week 30 (N=76,91,89,79,82,87,98) | -0.09 mg/dL | Standard Error 3.24 |
| Lina5Pio15 | Fasting Plasma Glucose (FPG) Change From Baseline by Visit Over Time | Change at week 18 (N=100,122,121,111,104,103,114) | -19.01 mg/dL | Standard Error 3.24 |
| Lina5Pio15 | Fasting Plasma Glucose (FPG) Change From Baseline by Visit Over Time | Change at week 24 (N=90,108,108,96,93,93,108) | -16.68 mg/dL | Standard Error 3.2 |
| Lina5Pio15 | Fasting Plasma Glucose (FPG) Change From Baseline by Visit Over Time | Change at week 6 (N=118,132,133,130,119,122,124) | -19.25 mg/dL | Standard Error 2.96 |
| Lina5Pio15 | Fasting Plasma Glucose (FPG) Change From Baseline by Visit Over Time | Change at week 12 (N=111,124,126,122,108,114,118) | -17.99 mg/dL | Standard Error 3.24 |
| Lina5Pio15 | Fasting Plasma Glucose (FPG) Change From Baseline by Visit Over Time | Change at week 30 (N=76,91,89,79,82,87,98) | -17.93 mg/dL | Standard Error 3.27 |
| Lina5Pio30 | Fasting Plasma Glucose (FPG) Change From Baseline by Visit Over Time | Change at week 30 (N=76,91,89,79,82,87,98) | -27.11 mg/dL | Standard Error 3.22 |
| Lina5Pio30 | Fasting Plasma Glucose (FPG) Change From Baseline by Visit Over Time | Change at week 24 (N=90,108,108,96,93,93,108) | -31.48 mg/dL | Standard Error 3.2 |
| Lina5Pio30 | Fasting Plasma Glucose (FPG) Change From Baseline by Visit Over Time | Change at week 18 (N=100,122,121,111,104,103,114) | -31.22 mg/dL | Standard Error 3.25 |
| Lina5Pio30 | Fasting Plasma Glucose (FPG) Change From Baseline by Visit Over Time | Change at week 12 (N=111,124,126,122,108,114,118) | -31.25 mg/dL | Standard Error 3.19 |
| Lina5Pio30 | Fasting Plasma Glucose (FPG) Change From Baseline by Visit Over Time | Change at week 6 (N=118,132,133,130,119,122,124) | -26.89 mg/dL | Standard Error 2.94 |
| Lina5Pio45 | Fasting Plasma Glucose (FPG) Change From Baseline by Visit Over Time | Change at week 18 (N=100,122,121,111,104,103,114) | -30.66 mg/dL | Standard Error 3.12 |
| Lina5Pio45 | Fasting Plasma Glucose (FPG) Change From Baseline by Visit Over Time | Change at week 6 (N=118,132,133,130,119,122,124) | -28.36 mg/dL | Standard Error 2.89 |
| Lina5Pio45 | Fasting Plasma Glucose (FPG) Change From Baseline by Visit Over Time | Change at week 24 (N=90,108,108,96,93,93,108) | -31.49 mg/dL | Standard Error 3.03 |
| Lina5Pio45 | Fasting Plasma Glucose (FPG) Change From Baseline by Visit Over Time | Change at week 30 (N=76,91,89,79,82,87,98) | -34.04 mg/dL | Standard Error 3.07 |
| Lina5Pio45 | Fasting Plasma Glucose (FPG) Change From Baseline by Visit Over Time | Change at week 12 (N=111,124,126,122,108,114,118) | -28.53 mg/dL | Standard Error 3.13 |
Secondary
HbA1c Change From Baseline by Visit Over Time
HbA1c is measured as a percentage. The change from baseline is the HbA1c over time minus the baseline HbA1c. The model includes fixed effects for treatment, continuous baseline HbA1c, prior andi-diabetic medication, country, visit and treatment. by visit interaction.
Time frame: Baseline, week 6, week 12, week 18, week 24, week 30
Population: FAS (observed cases)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pio15 | HbA1c Change From Baseline by Visit Over Time | Change to week 12 (N=112,124,127,122,111,117,120) | -0.47 percent | Standard Error 0.08 |
| Pio15 | HbA1c Change From Baseline by Visit Over Time | Change to week 6 (N=121,133,133,130,119,124,125) | -0.22 percent | Standard Error 0.06 |
| Pio15 | HbA1c Change From Baseline by Visit Over Time | Change to week 18 (N=101,121,122,112,104,104,115) | -0.63 percent | Standard Error 0.09 |
| Pio15 | HbA1c Change From Baseline by Visit Over Time | Change to week 30 (N=78,93,91,79,86,87,97) | -0.77 percent | Standard Error 0.09 |
| Pio15 | HbA1c Change From Baseline by Visit Over Time | Change to week 24 (N=91,108,110,95,92,96,109) | -0.75 percent | Standard Error 0.09 |
| Pio30 | HbA1c Change From Baseline by Visit Over Time | Change to week 18 (N=101,121,122,112,104,104,115) | -0.58 percent | Standard Error 0.08 |
| Pio30 | HbA1c Change From Baseline by Visit Over Time | Change to week 12 (N=112,124,127,122,111,117,120) | -0.43 percent | Standard Error 0.07 |
| Pio30 | HbA1c Change From Baseline by Visit Over Time | Change to week 24 (N=91,108,110,95,92,96,109) | -0.67 percent | Standard Error 0.09 |
| Pio30 | HbA1c Change From Baseline by Visit Over Time | Change to week 30 (N=78,93,91,79,86,87,97) | -0.73 percent | Standard Error 0.08 |
| Pio30 | HbA1c Change From Baseline by Visit Over Time | Change to week 6 (N=121,133,133,130,119,124,125) | -0.16 percent | Standard Error 0.06 |
| Pio45 | HbA1c Change From Baseline by Visit Over Time | Change to week 12 (N=112,124,127,122,111,117,120) | -0.59 percent | Standard Error 0.07 |
| Pio45 | HbA1c Change From Baseline by Visit Over Time | Change to week 6 (N=121,133,133,130,119,124,125) | -0.20 percent | Standard Error 0.06 |
| Pio45 | HbA1c Change From Baseline by Visit Over Time | Change to week 18 (N=101,121,122,112,104,104,115) | -0.82 percent | Standard Error 0.08 |
| Pio45 | HbA1c Change From Baseline by Visit Over Time | Change to week 30 (N=78,93,91,79,86,87,97) | -0.94 percent | Standard Error 0.09 |
| Pio45 | HbA1c Change From Baseline by Visit Over Time | Change to week 24 (N=91,108,110,95,92,96,109) | -0.87 percent | Standard Error 0.09 |
| Lina5 | HbA1c Change From Baseline by Visit Over Time | Change to week 12 (N=112,124,127,122,111,117,120) | -0.36 percent | Standard Error 0.08 |
| Lina5 | HbA1c Change From Baseline by Visit Over Time | Change to week 18 (N=101,121,122,112,104,104,115) | -0.39 percent | Standard Error 0.08 |
| Lina5 | HbA1c Change From Baseline by Visit Over Time | Change to week 6 (N=121,133,133,130,119,124,125) | -0.23 percent | Standard Error 0.06 |
| Lina5 | HbA1c Change From Baseline by Visit Over Time | Change to week 24 (N=91,108,110,95,92,96,109) | -0.39 percent | Standard Error 0.09 |
| Lina5 | HbA1c Change From Baseline by Visit Over Time | Change to week 30 (N=78,93,91,79,86,87,97) | -0.37 percent | Standard Error 0.09 |
| Lina5Pio15 | HbA1c Change From Baseline by Visit Over Time | Change to week 24 (N=91,108,110,95,92,96,109) | -0.84 percent | Standard Error 0.09 |
| Lina5Pio15 | HbA1c Change From Baseline by Visit Over Time | Change to week 30 (N=78,93,91,79,86,87,97) | -0.87 percent | Standard Error 0.09 |
| Lina5Pio15 | HbA1c Change From Baseline by Visit Over Time | Change to week 12 (N=112,124,127,122,111,117,120) | -0.71 percent | Standard Error 0.08 |
| Lina5Pio15 | HbA1c Change From Baseline by Visit Over Time | Change to week 6 (N=121,133,133,130,119,124,125) | -0.43 percent | Standard Error 0.06 |
| Lina5Pio15 | HbA1c Change From Baseline by Visit Over Time | Change to week 18 (N=101,121,122,112,104,104,115) | -0.81 percent | Standard Error 0.09 |
| Lina5Pio30 | HbA1c Change From Baseline by Visit Over Time | Change to week 24 (N=91,108,110,95,92,96,109) | -1.10 percent | Standard Error 0.09 |
| Lina5Pio30 | HbA1c Change From Baseline by Visit Over Time | Change to week 6 (N=121,133,133,130,119,124,125) | -0.47 percent | Standard Error 0.06 |
| Lina5Pio30 | HbA1c Change From Baseline by Visit Over Time | Change to week 30 (N=78,93,91,79,86,87,97) | -1.09 percent | Standard Error 0.09 |
| Lina5Pio30 | HbA1c Change From Baseline by Visit Over Time | Change to week 18 (N=101,121,122,112,104,104,115) | -1.07 percent | Standard Error 0.09 |
| Lina5Pio30 | HbA1c Change From Baseline by Visit Over Time | Change to week 12 (N=112,124,127,122,111,117,120) | -0.92 percent | Standard Error 0.08 |
| Lina5Pio45 | HbA1c Change From Baseline by Visit Over Time | Change to week 24 (N=91,108,110,95,92,96,109) | -1.23 percent | Standard Error 0.09 |
| Lina5Pio45 | HbA1c Change From Baseline by Visit Over Time | Change to week 6 (N=121,133,133,130,119,124,125) | -0.62 percent | Standard Error 0.06 |
| Lina5Pio45 | HbA1c Change From Baseline by Visit Over Time | Change to week 18 (N=101,121,122,112,104,104,115) | -1.22 percent | Standard Error 0.09 |
| Lina5Pio45 | HbA1c Change From Baseline by Visit Over Time | Change to week 12 (N=112,124,127,122,111,117,120) | -1.01 percent | Standard Error 0.08 |
| Lina5Pio45 | HbA1c Change From Baseline by Visit Over Time | Change to week 30 (N=78,93,91,79,86,87,97) | -1.27 percent | Standard Error 0.09 |
Secondary
Incidence of Rescue Therapy During the First 30 Weeks of Treatment
Rescue therapy was defined to include any new antidiabetic medication taken for hyperglycemia and introduced on or after the start date of study treatment and before the end date of study treatment.
Time frame: 30 weeks
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pio15 | Incidence of Rescue Therapy During the First 30 Weeks of Treatment | 20 participants |
| Pio30 | Incidence of Rescue Therapy During the First 30 Weeks of Treatment | 17 participants |
| Pio45 | Incidence of Rescue Therapy During the First 30 Weeks of Treatment | 11 participants |
| Lina5 | Incidence of Rescue Therapy During the First 30 Weeks of Treatment | 26 participants |
| Lina5Pio15 | Incidence of Rescue Therapy During the First 30 Weeks of Treatment | 12 participants |
| Lina5Pio30 | Incidence of Rescue Therapy During the First 30 Weeks of Treatment | 10 participants |
| Lina5Pio45 | Incidence of Rescue Therapy During the First 30 Weeks of Treatment | 5 participants |
Comparison: Treatment comparisons are for fixed dose combination versus monotherapy.p-value: 0.305295% CI: [0.284, 1.482]Regression, Logistic
Comparison: Treatment comparisons are for fixed dose combination versus monotherapy.p-value: 0.084495% CI: [0.187, 1.112]Regression, Logistic
Comparison: Treatment comparisons are for fixed dose combination versus monotherapy.p-value: 0.156195% CI: [0.143, 1.365]Regression, Logistic
Comparison: Treatment comparisons are for fixed dose combination versus monotherapy.p-value: 0.014695% CI: [0.165, 0.821]Regression, Logistic
Comparison: Treatment comparisons are for fixed dose combination versus monotherapy.p-value: 0.000995% CI: [0.102, 0.557]Regression, Logistic
Comparison: Treatment comparisons are for fixed dose combination versus monotherapy.p-value: 0.000295% CI: [0.05, 0.397]Regression, Logistic
Secondary
Occurrence of Cumulative Treat to Target Efficacy Response, of HbA1c Under Treatment of < 6.5% After 30 Weeks of Treatment
Glycosylated hemoglobin is reported as a percentage of the total hemoglobin.
Time frame: Baseline and 30 weeks
Population: FAS patients who also had baseline HbA1c \>=6.5%. Non-completers (patients without a value at Week 30) were considered as failures (NCF)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pio15 | Occurrence of Cumulative Treat to Target Efficacy Response, of HbA1c Under Treatment of < 6.5% After 30 Weeks of Treatment | 20 participants |
| Pio30 | Occurrence of Cumulative Treat to Target Efficacy Response, of HbA1c Under Treatment of < 6.5% After 30 Weeks of Treatment | 28 participants |
| Pio45 | Occurrence of Cumulative Treat to Target Efficacy Response, of HbA1c Under Treatment of < 6.5% After 30 Weeks of Treatment | 39 participants |
| Lina5 | Occurrence of Cumulative Treat to Target Efficacy Response, of HbA1c Under Treatment of < 6.5% After 30 Weeks of Treatment | 14 participants |
| Lina5Pio15 | Occurrence of Cumulative Treat to Target Efficacy Response, of HbA1c Under Treatment of < 6.5% After 30 Weeks of Treatment | 24 participants |
| Lina5Pio30 | Occurrence of Cumulative Treat to Target Efficacy Response, of HbA1c Under Treatment of < 6.5% After 30 Weeks of Treatment | 38 participants |
| Lina5Pio45 | Occurrence of Cumulative Treat to Target Efficacy Response, of HbA1c Under Treatment of < 6.5% After 30 Weeks of Treatment | 43 participants |
Comparison: Treatment comparisons are for fixed dose combination versus monotherapy.p-value: 0.735995% CI: [0.565, 2.243]Regression, Logistic
Comparison: Treatment comparisons are for fixed dose combination versus monotherapy.p-value: 0.036395% CI: [1.042, 3.484]Regression, Logistic
Comparison: Treatment comparisons are for fixed dose combination versus monotherapy.p-value: 0.403995% CI: [0.726, 2.217]Regression, Logistic
Comparison: Treatment comparisons are for fixed dose combination versus monotherapy.p-value: 0.034595% CI: [1.06, 4.649]Regression, Logistic
Comparison: Treatment comparisons are for fixed dose combination versus monotherapy.p-value: <0.000195% CI: [2.263, 9.266]Regression, Logistic
Comparison: Treatment comparisons are for fixed dose combination versus monotherapy.p-value: <0.000195% CI: [2.53, 10.145]Regression, Logistic
Secondary
Occurrence of Cumulative Treat to Target Efficacy Response, of HbA1c Under Treatment of < 7.0% After 30 Weeks of Treatment
Glycosylated hemoglobin is reported as a percentage of the total hemoglobin.
Time frame: Baseline and 30 weeks
Population: FAS patients who also had baseline HbA1c\>=7%.Non-completers (patients without a value at Week 30) were considered as failures (NCF).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pio15 | Occurrence of Cumulative Treat to Target Efficacy Response, of HbA1c Under Treatment of < 7.0% After 30 Weeks of Treatment | 39 participants |
| Pio30 | Occurrence of Cumulative Treat to Target Efficacy Response, of HbA1c Under Treatment of < 7.0% After 30 Weeks of Treatment | 55 participants |
| Pio45 | Occurrence of Cumulative Treat to Target Efficacy Response, of HbA1c Under Treatment of < 7.0% After 30 Weeks of Treatment | 68 participants |
| Lina5 | Occurrence of Cumulative Treat to Target Efficacy Response, of HbA1c Under Treatment of < 7.0% After 30 Weeks of Treatment | 29 participants |
| Lina5Pio15 | Occurrence of Cumulative Treat to Target Efficacy Response, of HbA1c Under Treatment of < 7.0% After 30 Weeks of Treatment | 45 participants |
| Lina5Pio30 | Occurrence of Cumulative Treat to Target Efficacy Response, of HbA1c Under Treatment of < 7.0% After 30 Weeks of Treatment | 61 participants |
| Lina5Pio45 | Occurrence of Cumulative Treat to Target Efficacy Response, of HbA1c Under Treatment of < 7.0% After 30 Weeks of Treatment | 81 participants |
Comparison: Treatment comparisons are for fixed dose combination versus monotherapy.p-value: 0.463995% CI: [0.692, 2.242]Regression, Logistic
Comparison: Treatment comparisons are for fixed dose combination versus monotherapy.p-value: 0.054695% CI: [0.989, 3.083]Regression, Logistic
Comparison: Treatment comparisons are for fixed dose combination versus monotherapy.p-value: 0.025495% CI: [1.083, 3.345]Regression, Logistic
Comparison: Treatment comparisons are for fixed dose combination versus monotherapy.p-value: 0.000995% CI: [1.524, 5.159]Regression, Logistic
Comparison: Treatment comparisons are for fixed dose combination versus monotherapy.p-value: <0.000195% CI: [2.947, 10.001]Regression, Logistic
Comparison: Treatment comparisons are for fixed dose combination versus monotherapy.p-value: <0.000195% CI: [5.187, 17.821]Regression, Logistic
Secondary
Occurrence of Relative Efficacy Response (HbA1c Lowering by at Least 0.5% After 30 Weeks of Treatment)
Glycosylated hemoglobin is reported as a percentage of the total hemoglobin.
Time frame: Baseline and 30 weeks
Population: FAS with non-completers (without a value at Week 30) considered as failure
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pio15 | Occurrence of Relative Efficacy Response (HbA1c Lowering by at Least 0.5% After 30 Weeks of Treatment) | 79 participants |
| Pio30 | Occurrence of Relative Efficacy Response (HbA1c Lowering by at Least 0.5% After 30 Weeks of Treatment) | 83 participants |
| Pio45 | Occurrence of Relative Efficacy Response (HbA1c Lowering by at Least 0.5% After 30 Weeks of Treatment) | 90 participants |
| Lina5 | Occurrence of Relative Efficacy Response (HbA1c Lowering by at Least 0.5% After 30 Weeks of Treatment) | 54 participants |
| Lina5Pio15 | Occurrence of Relative Efficacy Response (HbA1c Lowering by at Least 0.5% After 30 Weeks of Treatment) | 79 participants |
| Lina5Pio30 | Occurrence of Relative Efficacy Response (HbA1c Lowering by at Least 0.5% After 30 Weeks of Treatment) | 91 participants |
| Lina5Pio45 | Occurrence of Relative Efficacy Response (HbA1c Lowering by at Least 0.5% After 30 Weeks of Treatment) | 107 participants |
Comparison: Treatment comparisons are for fixed dose combination versus monotherapy.p-value: 0.75495% CI: [0.637, 1.863]Regression, Logistic
Comparison: Treatment comparisons are for fixed dose combination versus monotherapy.p-value: 0.050695% CI: [0.999, 2.918]Regression, Logistic
Comparison: Treatment comparisons are for fixed dose combination versus monotherapy.p-value: 0.000595% CI: [1.604, 5.485]Regression, Logistic
Comparison: Treatment comparisons are for fixed dose combination versus monotherapy.p-value: 0.000295% CI: [1.594, 4.559]Regression, Logistic
Comparison: Treatment comparisons are for fixed dose combination versus monotherapy.p-value: <0.000195% CI: [2.348, 6.873]Regression, Logistic
Comparison: Treatment comparisons are for fixed dose combination versus monotherapy.p-value: <0.000195% CI: [4.63, 15.681]Regression, Logistic
Secondary
Time to First Use of Rescue Therapy
Proportion of patients at 30 weeks with rescue therapy using Kaplan-Meier analysis.
Time frame: 30 weeks
Population: FAS
| Arm | Measure | Group | Value (NUMBER) | Dispersion |
|---|---|---|---|---|
| Pio15 | Time to First Use of Rescue Therapy | Proportion event-free | 0.8117 Proportion of participants | 50.5 |
| Pio15 | Time to First Use of Rescue Therapy | Standard Error | 0.0382 Proportion of participants | — |
| Pio30 | Time to First Use of Rescue Therapy | Proportion event-free | 0.8533 Proportion of participants | 47.8 |
| Pio30 | Time to First Use of Rescue Therapy | Standard Error | 0.0330 Proportion of participants | — |
| Pio45 | Time to First Use of Rescue Therapy | Proportion event-free | 0.9051 Proportion of participants | 55.3 |
| Pio45 | Time to First Use of Rescue Therapy | Standard Error | 0.0273 Proportion of participants | — |
| Lina5 | Time to First Use of Rescue Therapy | Proportion event-free | 0.7756 Proportion of participants | 47.7 |
| Lina5 | Time to First Use of Rescue Therapy | Standard Error | 0.0390 Proportion of participants | — |
| Lina5Pio15 | Time to First Use of Rescue Therapy | Proportion event-free | 0.8854 Proportion of participants | 61.5 |
| Lina5Pio15 | Time to First Use of Rescue Therapy | Standard Error | 0.0313 Proportion of participants | — |
| Lina5Pio30 | Time to First Use of Rescue Therapy | Proportion event-free | 0.9078 Proportion of participants | 54.7 |
| Lina5Pio30 | Time to First Use of Rescue Therapy | Standard Error | 0.0279 Proportion of participants | — |
| Lina5Pio45 | Time to First Use of Rescue Therapy | Proportion event-free | 0.9548 Proportion of participants | 65.7 |
| Lina5Pio45 | Time to First Use of Rescue Therapy | Standard Error | 0.0198 Proportion of participants | — |
Secondary
Two-hour Postprandial Glucose (2hPPG) Change From Baseline at Week 30 by Meal Tolerance Test (MTT)
The change from baseline is the 2hPPG after 30 weeks minus the baseline 2hPPG.
Time frame: Baseline and 30 weeks
Population: MTT set: This patient set includes those patients in the FAS who had a valid MTT at baseline and at least one valid on-treatment MTT. An MTT is considered valid if both an FPG and a 2-hour PPG value are available.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pio15 | Two-hour Postprandial Glucose (2hPPG) Change From Baseline at Week 30 by Meal Tolerance Test (MTT) | -30.65 mg/dL | Standard Error 10.93 |
| Pio30 | Two-hour Postprandial Glucose (2hPPG) Change From Baseline at Week 30 by Meal Tolerance Test (MTT) | -83.00 mg/dL | Standard Error 9.85 |
| Pio45 | Two-hour Postprandial Glucose (2hPPG) Change From Baseline at Week 30 by Meal Tolerance Test (MTT) | -82.98 mg/dL | Standard Error 10.92 |
| Lina5 | Two-hour Postprandial Glucose (2hPPG) Change From Baseline at Week 30 by Meal Tolerance Test (MTT) | -51.61 mg/dL | Standard Error 11.67 |
| Lina5Pio15 | Two-hour Postprandial Glucose (2hPPG) Change From Baseline at Week 30 by Meal Tolerance Test (MTT) | -67.26 mg/dL | Standard Error 11.15 |
| Lina5Pio30 | Two-hour Postprandial Glucose (2hPPG) Change From Baseline at Week 30 by Meal Tolerance Test (MTT) | -87.94 mg/dL | Standard Error 11.14 |
| Lina5Pio45 | Two-hour Postprandial Glucose (2hPPG) Change From Baseline at Week 30 by Meal Tolerance Test (MTT) | -84.77 mg/dL | Standard Error 10.28 |
Comparison: Treatment comparisons are for fixed dose combination versus monotherapy.p-value: 0.005795% CI: [-62.42, -10.8]ANCOVA
Comparison: Treatment comparisons are for fixed dose combination versus monotherapy.p-value: 0.702195% CI: [-30.39, 20.51]ANCOVA
Comparison: Treatment comparisons are for fixed dose combination versus monotherapy.p-value: 0.893295% CI: [-27.95, 24.38]ANCOVA
Comparison: Treatment comparisons are for fixed dose combination versus monotherapy.p-value: 0.270695% CI: [-43.6, 12.3]ANCOVA
Comparison: Treatment comparisons are for fixed dose combination versus monotherapy.p-value: 0.012695% CI: [-64.78, -7.89]ANCOVA
Comparison: Treatment comparisons are for fixed dose combination versus monotherapy.p-value: 0.016795% CI: [-60.23, -6.08]ANCOVA