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The primary objective of this exploratory meta-analysis is to evaluate the frequencies, incidence rates, and hazard ratios of lower-limb amputation (LLA) events (primary outcome) and of adverse events related to amputation (secondary outcome) in patients treated with empagliflozin compared with placebo in the pooled population of the long-term studies 1245.25, 1245.110, and 1245.121 (SAF-M1), in the pooled population of studies 1245.110 and 1245.121 (SAFM2), and in each of the 3 studies separately.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| EMPA-REG - Placebo | Participants of the EMP-REG OUTCOME study (1245.25) who received placebo. |
| |
| EMPA-REG - Empagliflozin low dose | Participants of the EMPA-REG OUTCOME study (1245.25) who received a low dose of empagliflozin once daily (QD). |
| |
| EMPA-REG - Empagliflozin high dose | Participants of the EMP-REG OUTCOME study (1245.25) who received a high dose of empagliflozin once daily (QD). |
| |
| EMPEROR-Preserved - Empagliflozin | Participants of the EMPEROR-Preserved study (1245.110) who received empagliflozin once daily (QD). |
| |
| EMPEROR-Preserved - Placebo | Participants of the EMPEROR-Preserved study (1245.110) who received placebo once daily (QD). |
| |
| EMPEROR-Reduced - Empagliflozin | Participants of the EMPEROR-Reduced study (1245.121) who received empagliflozin once daily (QD). |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Placebo | Drug | Placebo |
|
| Measure | Description | Time Frame |
|---|---|---|
| Incidence Rate of Lower Limb Amputation (LLA) | Incidence rate of lower limb amputation (LLA). Incidence rate were provided as rate per 100 patients-years (pt-yrs) calculated as the observed number of patients with event divided by observed time-at-risk over all patients. Time at risk was derived as followed: Patient with event: time at risk in days = date of start of first event - treatment start date + 1. Patients without event: time at risk in days = last date on treatment + 7 days - treatment start date + 1. Abbreviation: pt-yrs = patient-years. | From first to last dose of study medication plus 7 days to account for the residual drug effect, up to 1639 days. |
| Measure | Description | Time Frame |
|---|---|---|
| Incidence Rate of Adverse Events Related to Amputation | Incidence rate of adverse events (AEs) related to amputation. Incidence rate were provided as rate per 100 patients-years (pt-yrs) calculated as the observed number of patients with event divided by observed time-at-risk over all patients. Time at risk was derived as followed: Patient with event: time at risk in days = date of start of first event - treatment start date + 1. Patients without event: time at risk in days = last date on treatment + 7 days - treatment start date + 1. A search with a pre-defined list of MedDRA preferred terms was performed to identify all AEs related to amputation. These AE included vascular disorders, diabetic-foot-related events, wound/infections, nervous system disorders and volume depletion events. Abbreviation: pt-yrs = patient-years. |
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Inclusion Criteria for 1245.25:
Age ≥18 years, diagnosis of type 2 diabetes mellitus (T2DM)
Drug-naïve or pretreated with any background therapy
Glycated haemoglobin (HbA1c) criteria
Body mass index (BMI) ≤45 kg/m2
With high cardiovascular risk, defined as ≥1 of the following criteria
Inclusion criteria for 1245.110 and 1245.121
Age ≥18 years (Japan, age ≥20 years)
Chronic heart failure (HF) new york hear association (NYHA) class II to IV
Ejection fraction (EF) and N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) criteria
1245.110 only: structural heart disease within 6 months or documented hospitalisation for HF within 12 months prior to screening
1245.121 only: stable dose of medical therapy for HF consistent with local and international cardiology guidelines
Exclusion criteria for 1245.25
Exclusion criteria for 1245.110 and 1245.121
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Patients with type 2 diabetes mellitus and increased cardiovascular risk (1245.25), patients with chronic heart failure with preserved ejection fraction (1245.110), and patients with chronic heart failure with reduced ejection fraction (1245.121), who were either treated with empagliflozin or placebo.
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Boehringer Ingelheim | Ingelheim | 55218 | Germany |
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| Label | URL |
|---|---|
| Related Info | View source |
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Clinical studies sponsored by Boehringer Ingelheim, phases I to IV, interventional and non-interventional, are in scope for sharing of the raw clinical study data and clinical study documents. Exceptions might apply, e.g. studies in products where Boehringer Ingelheim is not the license holder; studies regarding pharmaceutical formulations and associated analytical methods, and studies pertinent to pharmacokinetics using human biomaterials; studies conducted in a single center or targeting rare diseases (in case of low number of patients and therefore limitations with anonymization).
For more details refer to: https://www.mystudywindow.com/msw/datatransparency
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As this is a meta-analysis of three independent trials, all subjects were screened for eligibility prior to participation of the respective trial.
This meta-analysis includes three randomised, placebo-controlled, double-blind, parallel-group and event-driven studies (NCT01131676, NCT03057951, NCT03057977) to evaluate the risk of lower-limb amputation (LLA) in patients treated with empagliflozin compared to placebo in the pooled population (SAF-M1 vs. SAF-M2).
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| ID | Title | Description |
|---|---|---|
| FG000 | Trial NCT01131676: Placebo | Oral administration of Placebo matching empagliflozin 10 or 25 milligram (mg) (1 tablet once daily) in patients with type 2 diabetes mellitus (T2DM). |
| FG001 | Trial NCT01131676: Empagliflozin 10 mg |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Apr 10, 2019 | Jul 4, 2022 |
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|
| EMPEROR-Reduced - Placebo | Participants of the EMPEROR-Reduced study (1245.121) who received placebo once daily (QD). |
|
| Empagliflozin | Drug | Empagliflozin once daily |
|
| From first to last dose of study medication plus 7 days to account for the residual drug effect, up to 1639 days. |
1 film-coated tablet of 10 mg empagliflozin (BI 10773) was administered orally once daily in patients with T2DM.
| FG002 | Trial NCT01131676: Empagliflozin 25 mg | 1 film-coated tablet of 25 mg empagliflozin (BI 10773) was administered orally once daily in patients with T2DM. |
| FG003 | Trial NCT03057951: Placebo | 1 film-coated tablet of matching placebo was administered orally once daily in patients with chronic heart failure with preserved ejection fraction (HFpEF). |
| FG004 | Trial NCT03057951: Empagliflozin 10 mg | 1 film-coated tablet of 10 milligram (mg) of empagliflozin (BI 10773) was administered orally once daily in patients with chronic heart failure with preserved ejection fraction (HFpEF). |
| FG005 | Trial NCT03057977: Placebo | 1 film-coated tablet of matching placebo was administered orally once daily in patients with heart failure with reduced ejection fraction (HFrEF). |
| FG006 | Trial NCT03057977: Empagliflozin 10 mg | 1 film-coated tablet of 10 milligram (mg) empagliflozin (BI 10773) was administered orally once daily in patients with heart failure with reduced ejection fraction (HFrEF). |
| Treated |
|
| COMPLETED |
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| NOT COMPLETED |
|
|
Treated Set (TS): Patients treated with at least 1 dose of study medication.
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| ID | Title | Description |
|---|---|---|
| BG000 | Trial NCT01131676: Placebo | Oral administration of Placebo matching empagliflozin 10 or 25 milligram (mg) (1 tablet once daily) in patients with type 2 diabetes mellitus (T2DM). |
| BG001 | Trial NCT01131676: Empagliflozin 10 mg | 1 film-coated tablet of 10 mg empagliflozin (BI 10773) was administered orally once daily in patients with T2DM. |
| BG002 | Trial NCT01131676: Empagliflozin 25 mg | 1 film-coated tablet of 25 mg empagliflozin (BI 10773) was administered orally once daily in patients with T2DM. |
| BG003 | Trial NCT03057951: Placebo | 1 film-coated tablet of matching placebo was administered orally once daily in patients with chronic heart failure with preserved ejection fraction (HFpEF). |
| BG004 | Trial NCT03057951: Empagliflozin 10 mg | 1 film-coated tablet of 10 milligram (mg) of empagliflozin (BI 10773) was administered orally once daily in patients with chronic heart failure with preserved ejection fraction (HFpEF). |
| BG005 | Trial NCT03057977: Placebo | 1 film-coated tablet of matching placebo was administered orally once daily in patients with heart failure with reduced ejection fraction (HFrEF). |
| BG006 | Trial NCT03057977: Empagliflozin 10 mg | 1 film-coated tablet of 10 milligram (mg) empagliflozin (BI 10773) was administered orally once daily in patients with heart failure with reduced ejection fraction (HFrEF). |
| BG007 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | Years |
| |||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
| ||||||||||||||||
| Race (NIH/OMB) | Count of Participants | Participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Secondary | Incidence Rate of Adverse Events Related to Amputation | Incidence rate of adverse events (AEs) related to amputation. Incidence rate were provided as rate per 100 patients-years (pt-yrs) calculated as the observed number of patients with event divided by observed time-at-risk over all patients. Time at risk was derived as followed: Patient with event: time at risk in days = date of start of first event - treatment start date + 1. Patients without event: time at risk in days = last date on treatment + 7 days - treatment start date + 1. A search with a pre-defined list of MedDRA preferred terms was performed to identify all AEs related to amputation. These AE included vascular disorders, diabetic-foot-related events, wound/infections, nervous system disorders and volume depletion events. Abbreviation: pt-yrs = patient-years. | Treated Set: Patients treated with at least 1 dose of study medication. Results are reported by the pooled population (SAF-M1 and SAF-M2) and for each study separately. For trial NCT01131676, 10 mg and 25 mg were combined, as the overall safety profile is similar for empagliflozin 10 mg and 25 mg. This approach was agreed with the European Medicines Agency (EMA). | Posted | Number | 95% Confidence Interval | Patients with events per 100 pt-yrs | From first to last dose of study medication plus 7 days to account for the residual drug effect, up to 1639 days. |
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| Primary | Incidence Rate of Lower Limb Amputation (LLA) | Incidence rate of lower limb amputation (LLA). Incidence rate were provided as rate per 100 patients-years (pt-yrs) calculated as the observed number of patients with event divided by observed time-at-risk over all patients. Time at risk was derived as followed: Patient with event: time at risk in days = date of start of first event - treatment start date + 1. Patients without event: time at risk in days = last date on treatment + 7 days - treatment start date + 1. Abbreviation: pt-yrs = patient-years. | Treated Set: Patients treated with at least 1 dose of study medication. Results are reported by the pooled population (SAF-M1 and SAF-M2) and for each study separately. For trial NCT01131676, 10 mg and 25 mg were combined, as the overall safety profile is similar for empagliflozin 10 mg and 25 mg. This approach was agreed with the European Medicines Agency (EMA). | Posted | Number | 95% Confidence Interval | Patients with events per 100pt-yrs | From first to last dose of study medication plus 7 days to account for the residual drug effect, up to 1639 days. |
|
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As this is a meta-analysis adverse events were not planned to be collected and reported. Adverse events of each study (NCT01131676, NCT03057951, NCT03057977) included in this meta-analysis have already been disclosed.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | SAF-M1 Placebo | Safety analysis grouping (SAF)-M1 - Placebo included the pooled population of all three studies. Patients with type 2 diabetes mellitus (T2DM) (NCT01131676), patients with heart failure with preserved ejection fraction (HFpEF) (NCT03057951) and patients with heart failure with reduced ejection fraction (HFrEF) (NCT03057977) treated with placebo. In all three trials, 1 film-coated tablet of placebo matching empagliflozin was administered orally once daily. | 0 | 0 | 0 | 0 | 0 | 0 |
| EG001 | SAF-M1 Empagliflozin 10 mg | Safety analysis grouping (SAF)-M1 Empagliflozin 10 mg included the pooled population of all three studies. Patients with T2DM (NCT01131676), patients with HFpEF (NCT03057951) and patients with HFrEF (NCT03057977) treated with 10 milligram (mg) empagliflozin. In all three trials, a film-coated tablet of 10 mg Empagliflozin was administered orally once daily. | 0 | 0 | 0 | 0 | 0 | 0 |
| EG002 | SAF-M1 Empagliflozin 25 mg | Safety analysis grouping (SAF)-M1 Empagliflozin 25 mg included the pooled population of trial NCT01131676. Patients were administered one film-coated tablet of 25 milligram (mg) empagliflozin orally once daily. | 0 | 0 | 0 | 0 | 0 | 0 |
| EG003 | SAF-M2 Placebo | SAF-M2 included the pooled population of the 2 chronic heart failure studies (NCT03057951, NCT03057977). Patients with HFpEF and patients with HFrEF treated with placebo. In both trials, 1 film-coated tablet of placebo matching empagliflozin was administered orally once daily. | 0 | 0 | 0 | 0 | 0 | 0 |
| EG004 | SAF-M2 Empagliflozin 10 mg | SAF-M2 included the pooled population of the 2 chronic heart failure studies (NCT03057951, NCT03057977). Patients with HFpEF and patients with HFrEF treated with 10 mg empagliflozin, administered as film-coated tablet orally once daily. | 0 | 0 | 0 | 0 | 0 | 0 |
| EG005 | Trial NCT01131676: Placebo | Oral administration of Placebo matching empagliflozin 10 or 25 milligram (mg) (1 tablet once daily) in patients with type 2 diabetes mellitus (T2DM). | 0 | 0 | 0 | 0 | 0 | 0 |
| EG006 | Trial NCT01131676: Empagliflozin 10 mg | 1 film-coated tablet of 10 mg empagliflozin (BI 10773) was administered orally once daily in patients with T2DM. | 0 | 0 | 0 | 0 | 0 | 0 |
| EG007 | Trial NCT01131676: Empagliflozin 25 mg | 1 film-coated tablet of 25 mg empagliflozin (BI 10773) was administered orally once daily in patients with T2DM. | 0 | 0 | 0 | 0 | 0 | 0 |
| EG008 | Trial NCT03057977: Placebo | 1 film-coated tablet of matching placebo was administered orally once daily in patients with heart failure with reduced ejection fraction (HFrEF). | 0 | 0 | 0 | 0 | 0 | 0 |
| EG009 | Trial NCT03057977: Empagliflozin 10 mg | 1 film-coated tablet of 10 milligram (mg) empagliflozin (BI 10773) was administered orally once daily in patients with heart failure with reduced ejection fraction (HFrEF). | 0 | 0 | 0 | 0 | 0 | 0 |
| EG010 | Trial NCT03057951: Placebo | 1 film-coated tablet of matching placebo was administered orally once daily in patients with chronic heart failure with preserved ejection fraction (HFpEF). | 0 | 0 | 0 | 0 | 0 | 0 |
| EG011 | Trial NCT03057951: Empagliflozin 10 mg | 1 film-coated tablet of 10 milligram (mg) of empagliflozin (BI 10773) was administered orally once daily in patients with chronic heart failure with preserved ejection fraction (HFpEF). | 0 | 0 | 0 | 0 | 0 | 0 |
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For study NCT01131676, events leading to LLA were not prespecified but were identified during unblinded medical review of data. Also, since both empagliflozin arms (10 and 25 mg) of study NCT01131676 were combined for the pooled SAF-M1 analysis, this led not only to a different sample size, but also to different patient populations for placebo and empagliflozin, respectively.
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Boehringer Ingelheim | Boehringer Ingelheim, Call Center | 018002430127 | clintriage.rdg@boehringer-ingelheim.com |
| Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Apr 10, 2019 | Jul 4, 2022 | SAP_001.pdf |
| ID | Term |
|---|---|
| D003924 | Diabetes Mellitus, Type 2 |
| ID | Term |
|---|---|
| D003920 | Diabetes Mellitus |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D004700 | Endocrine System Diseases |
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| ID | Term |
|---|---|
| C570240 | empagliflozin |
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| Male |
|
| Not Hispanic or Latino |
|
| Unknown or Not Reported |
|
| Asian |
|
| Native Hawaiian or Other Pacific Islander |
|
| Black or African American |
|
| White |
|
| More than one race |
|
| Unknown or Not Reported |
|
1 film-coated tablet of 10 mg or 25 mg empagliflozin (BI 10773) was administered orally once daily in patients with T2DM. |
| OG006 | Trial NCT03057951: Placebo | 1 film-coated tablet of matching placebo was administered orally once daily in patients with chronic heart failure with preserved ejection fraction (HFpEF). |
| OG007 | Trial NCT03057951: Empagliflozin 10 mg | 1 film-coated tablet of 10 milligram (mg) of empagliflozin (BI 10773) was administered orally once daily in patients with chronic heart failure with preserved ejection fraction (HFpEF). |
| OG008 | Trial NCT03057977: Placebo | 1 film-coated tablet of matching placebo was administered orally once daily in patients with heart failure with reduced ejection fraction (HFrEF). |
| OG009 | Trial NCT03057977: Empagliflozin 10 mg | 1 film-coated tablet of 10 milligram (mg) empagliflozin (BI 10773) was administered orally once daily in patients with heart failure with reduced ejection fraction (HFrEF). |
| Diabetic foot related AE |
|
| Infections potentially related to LLA |
|
| Wound/infection |
|
| Nervous system disorder |
|
| Volume depletion |
|
Time to first vascular AE (SAF-M2) |
| Regression, Cox |
Cox regression of time to first vascular AE. Cox regression model with terms for study, baseline diabetes status and treatment. |
| 0.7474 |
| Hazard Ratio (HR) |
| 0.95 |
| 2-Sided |
| 95 |
| 0.72 |
| 1.27 |
Comparison versus placebo. [Treatment/Placebo]. |
| Other |
| Time to first vascular AE (Trial NCT01131676, all empagliflozin (10 and 25 mg vs. Placebo)) | Regression, Cox | Cox regression for time to first vascular AE on-treatment. Cox regression model with a term for treatment. | 0.7943 | Hazard Ratio (HR) | 1.03 | 2-Sided | 95 | 0.81 | 1.31 | Comparison vs. Placebo [Treatment / Placebo] | Other |
| Time to first vascular AE (Trial NCT03057951) | Regression, Cox | Cox regression for time to first vascular AE on-treatment. Cox regression model with terms for baseline diabetes status and treatment. | 0.8518 | Hazard Ratio (HR) | 0.97 | 2-Sided | 95 | 0.69 | 1.36 | Comparison vs. Placebo [Treatment / Placebo]. | Other |
| Time to first vascular AE (Trial NCT03057977) | Regression, Cox | Cox regression for time to first vascular AE on-treatment. Cox regression model with terms for baseline diabetes status and treatment. | 0.7660 | Hazard Ratio (HR) | 0.93 | 2-Sided | 95 | 0.56 | 1.53 | Comparison vs Placebo [Treatment/Placebo] | Other |
| Time to first diabetic foot related AE (SAF-M1) | Regression, Cox | Cox regression of time to first diabetic foot related AE. Cox regression model with terms for study, baseline diabetes status and treatment. | 0.3612 | Hazard Ratio (HR) | 1.15 | 2-Sided | 95 | 0.85 | 1.55 | Comparison versus placebo [Treatment/Placebo]. | Other |
| Time to first diabetic foot related AE (SAF-M2) | Regression, Cox | Cox regression of time to first diabetic foot related AE. Cox regression model with terms for study, baseline diabetes status and treatment. | 0.1610 | Hazard Ratio (HR) | 1.44 | 2-Sided | 95 | 0.86 | 2.40 | Comparison versus Placebo [Treatment/Placebo]. | Other |
| Time to first diabetic foot related AE (Trial NCT01131676, all empagliflozin (10 and 25 mg) vs. Placebo) | Regression, Cox | Cox regression for time to first diabetic foot related AE on treatment. Cox regression model with a term for treatment. | 0.9128 | Hazard Ratio (HR) | 1.02 | 2-Sided | 95 | 0.71 | 1.47 | Comparison vs. Placebo [Treatment/Placebo] | Other |
| Time to first diabetic foot related AE (Trial NCT03057951) | Regression, Cox | Cox regression for time to first diabetic foot related AE. Cox regression model with terms for baseline diabetes status and treatment. | 0.5276 | Hazard Ratio (HR) | 0.81 | 2-Sided | 95 | 0.43 | 1.54 | Comparison vs. Placebo [Treatment/Placebo] | Other |
| Time to first diabetic foot related AE (Trial NCT03057977) | Regression, Cox | Cox regression for time to first diabetic foot related AE. Cox regression model with terms for baseline diabetes status and treatment. | 0.0048 | Hazard Ratio (HR) | 4.72 | 2-Sided | 95 | 1.60 | 13.87 | Comparison vs Placebo [Treatment / Placebo] | Other |
| Time to first infections potentially related to LLA's (SAF-M1) | Regression, Cox | Cox regression of time to first infections potentially related to LLA's. Cox regression with terms for study, baseline diabetes status and treatment. | 0.1526 | Hazard Ratio (HR) | 0.89 | 2-Sided | 95 | 0.77 | 1.04 | Comparison versus Placebo [Treatment/Placebo]. | Other |
| Time to first infection potentially related to LLA's (SAF-M2) | Regression, Cox | Cox regression of time to first infection potentially related to LLA's. Cox regression with terms for study, baseline diabetes status and treatment. | 0.7430 | Hazard Ratio (HR) | 0.96 | 2-Sided | 95 | 0.76 | 1.21 | Comparison versus Placebo [Treatment/Placebo]. | Other |
| Time to first infections potentially related to LLA (Trial NCT01131676, all Empagliflozin (10 mg and 25 mg) vs. Placebo) | Regression, Cox | Cox regression for infections potentially related to LLA-on treatment. Cox regression model with a term for treatment. | 0.1049 | Hazard Ratio (HR) | 0.85 | 2-Sided | 95 | 0.69 | 1.04 | Comparison vs Placebo [Treatment/Placebo] | Other |
| Time to first infections potentially related to LLA (Trial NCT03057951) | Regression, Cox | Cox regression for infections potentially related to LLA on treatment. Cox regression model with terms for baseline diabetes status and treatment. | 0.3950 | Hazard Ratio (HR) | 0.89 | 2-Sided | 95 | 0.67 | 1.17 | Comparison vs Placebo [Treatment/Placebo] | Other |
| Time to first infections potentially related to LLA (Trial NCT03057977) | Regression, Cox | Cox regression for infections potentially related to LLA on-treatment. Cox regression model with terms for baseline diabetes status and treatment. | 0.4429 | Hazard Ratio (HR) | 1.19 | 2-Sided | 95 | 0.76 | 1.87 | Comparison vs Placebo [Treatment/Placebo] | Other |
| Time to first wound/infection (SAF-M1) | Regression, Cox | Cox regression of time to first wound infections. Cox regression with terms for study, baseline diabetes status and treatment. | 0.3396 | Hazard Ratio (HR) | 0.89 | 2-Sided | 95 | 0.70 | 1.13 | Comparison versus Placebo [Treatment/Placebo]. | Other |
| Time to first wound/infection (SAF-M2) | Regression, Cox | Cox regression of time to first wound infections. Cox regression with terms for study, baseline diabetes status and treatment | 0.1050 | Hazard Ratio (HR) | 0.70 | 2-Sided | 95 | 0.46 | 1.08 | Comparison versus Placebo [Treatment/Placebo]. | Other |
| Time to first wound/infection (Trial NCT01131676, all Empagliflozin (10 mg and 25 mg) vs Placebo) | Regression, Cox | Cox regression for time to first wound/infection on-treatment. | 0.9919 | Hazard Ratio (HR) | 1.00 | 2-Sided | 95 | 0.74 | 1.35 | Comparison vs Placebo [Treatment/Placebo] | Other |
| Time to first wound/infection (Trial NCT03057951) | Regression, Cox | Cox regression for time to first wound/infection on-treatment. Cox regression model with terms for baseline diabetes status and treatment. | 0.3634 | Hazard Ratio (HR) | 0.79 | 2-Sided | 95 | 0.48 | 1.31 | Comparison vs Placebo [Treatment/Placebo] | Other |
| Time to first wound/infection (Trial NCT03057977) | Regression, Cox | Cox regression for time to first wound/infection on-treatment. Cox regression model with terms for baseline diabetes status and treatment. | 0.1177 | Hazard Ratio (HR) | 0.52 | 2-Sided | 95 | 0.23 | 1.18 | Comparison vs Placebo [Treatment/Placebo] | Other |
| Time to first nervous system disorder (SAF-M1) | Regression, Cox | Cox regression of time to first nervous system disorder. Cox regression with terms for study, baseline diabetes status and treatment. | 0.9992 | Hazard Ratio (HR) | 1.00 | 2-Sided | 95 | 0.84 | 1.19 | Comparison versus Placebo [Treatment/Placebo]. | Other |
| Time to first nervous system disorder (SAF-M2) | Regression, Cox | Cox regression of time to first nervous system disorder. Cox regression model with terms for study, baseline diabetes status and treatment. | 0.6274 | Hazard Ratio (HR) | 1.09 | 2-Sided | 95 | 0.78 | 1.52 | Comparison versus Placebo [Treatment/Placebo]. | Other |
| Time to first nervous system disorder (Trial NCT01131676, all Empagliflozin (10 mg and 25 mg) vs Placebo) | Regression, Cox | Cox regression for time to first nervous system disorder on-treatment. Cox regression model with a term for treatment. | 0.7597 | Hazard Ratio (HR) | 0.97 | 2-Sided | 95 | 0.79 | 1.19 | Comparison vs Placebo [Treatment/Placebo] | Other |
| Time to first nervous system disorder (Trial NCT03057951) | Regression, Cox | Cox regression for time to first nervous system disorder on-treatment. Cox regression model with terms for baseline diabetes status and treatment. | 0.7067 | Hazard Ratio (HR) | 1.08 | 2-Sided | 95 | 0.74 | 1.57 | Comparison vs Placebo [Treatment/Placebo] | Other |
| time to first nervous system disorder (Trial NCT03057977) | Regression, Cox | Cox regression for time to first nervous system disorder on-treatment. Cox regression model with terms for baseline diabetes status and treatment. | 0.7404 | Hazard Ratio (HR) | 1.12 | 2-Sided | 95 | 0.56 | 2.25 | Comparison vs Placebo [Treatment/Placebo] | Other |
| Time to first volume depletion AE (SAF-M1) | Regression, Cox | Cox regression of time to first volume depletion AE. Cox regression model with terms for study, baseline diabetes status and treatment. | 0.1765 | Hazard Ratio (HR) | 1.21 | 2-Sided | 95 | 0.92 | 1.58 | Comparison versus Placebo [Treatment/Placebo]. | Other |
| Time to first volume depletion AE (SAF-M2) | Regression, Cox | Cox regression of time to first volume depletion AE. Cox regression with terms for study, baseline diabetes status and treatment. | 0.1978 | Hazard Ratio (HR) | 1.22 | 2-Sided | 95 | 0.90 | 1.66 | Comparison versus Placebo [Treatment/Placebo]. | Other |
| Time to first volume depletion (Trial NCT01131676, all Empagliflozin (10 mg and 25 mg) vs Placebo) | Regression, Cox | Cox regression for time to first volume depletion on-treatment. Cox regression model with a term for treatment. | 0.6561 | Hazard Ratio (HR) | 1.14 | 2-Sided | 95 | 0.64 | 2.05 | Comparison vs Placebo [Treatment/Placebo] | Other |
| Time to first volume depletion (Trial NCT03057951) | Regression, Cox | Cox regression for time to first volume depletion on-treatment. Cox regression model with terms for baseline diabetes status and treatment. | 0.1699 | Hazard Ratio (HR) | 1.29 | 2-Sided | 95 | 0.90 | 1.87 | Comparison vs Placebo [Treatment/Placebo] | Other |
| Time to first volume depletion (Trial NCT03057977) | Regression, Cox | Cox regression for time to first volume depletion on-treatment. Cox regression model with terms for baseline diabetes status and treatment. | 0.7944 | Hazard Ratio (HR) | 1.08 | 2-Sided | 95 | 0.62 | 1.87 | Comparison vs Placebo [Treatment/Placebo] | Other |
| OG001 |
| SAF-M1 Empagliflozin |
Safety analysis grouping (SAF)-M1 included the pooled population of all three studies. Patients with T2DM (NCT01131676), patients with HFpEF (NCT03057951) and patients with HFrEF (NCT03057977) treated with 10 milligram (mg) or 25 mg empagliflozin. |
| OG002 | SAF-M2 Placebo | SAF-M2 included the pooled population of the 2 chronic heart failure studies (NCT03057951, NCT03057977). Patients with HFpEF and patients with HFrEF treated with placebo. In both trials, 1 film-coated tablet of placebo matching empagliflozin was administered orally once daily. |
| OG003 | SAF-M2 Empagliflozin 10 mg | SAF-M2 included the pooled population of the 2 chronic heart failure studies (NCT03057951, NCT03057977). Patients with HFpEF and patients with HFrEF treated with 10 mg empagliflozin, administered as film-coated tablet orally once daily. |
| OG004 | Trial NCT01131676: Placebo | Oral administration of Placebo matching empagliflozin 10 or 25 milligram (mg) (1 tablet once daily) in patients with type 2 diabetes mellitus (T2DM). |
| OG005 | Trial NCT01131676: Empagliflozin 10 mg or 25 mg | 1 film-coated tablet of 10 mg or 25 mg empagliflozin (BI 10773) was administered orally once daily in patients with T2DM. |
| OG006 | Trial NCT03057951: Placebo | 1 film-coated tablet of matching placebo was administered orally once daily in patients with chronic heart failure with preserved ejection fraction (HFpEF). |
| OG007 | Trial NCT03057951: Empagliflozin 10 mg | 1 film-coated tablet of 10 milligram (mg) of empagliflozin (BI 10773) was administered orally once daily in patients with chronic heart failure with preserved ejection fraction (HFpEF). |
| OG008 | Trial NCT03057977: Placebo | 1 film-coated tablet of matching placebo was administered orally once daily in patients with heart failure with reduced ejection fraction (HFrEF). |
| OG009 | Trial NCT03057977: Empagliflozin 10 mg | 1 film-coated tablet of 10 milligram (mg) empagliflozin (BI 10773) was administered orally once daily in patients with heart failure with reduced ejection fraction (HFrEF). |
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