This Study Combines Data From 3 Other Studies Testing Empagliflozin in Patients With Diabetes or With Chronic Heart Failure. The Study Looks at the Numbers of Patients Who Had Lower Limb Amputations

Diabetes Mellitus, Type 2 Clinical Trial

Official title:

A Meta-Analysis of Amputation Risk in Empagliflozin Studies (1245.25, 1245.110, 1245.121)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04937816
• Other study ID #: 1245-0171
• Status: Completed
• Start date: June 1, 2021
• Est. completion date: July 13, 2021

Study information

• Verified date: June 2023
• Source: Boehringer Ingelheim
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 16746
• Est. completion date: July 13, 2021
• Est. primary completion date: July 13, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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
• Patients who were drug-naïve: HbA1c of 7 to 10%
• Patients with background therapy: HbA1c of 7 to 9%
• Body mass index (BMI) =45 kg/m2
• With high cardiovascular risk, defined as =1 of the following criteria
• History of myocardial infarction (>2 months prior to enrollment)
• Multi-vessel coronary artery disease: =2 major vessels or left main coronary artery
• Single-vessel coronary artery disease with no scheduled revascularization/previously unsuccessful revascularization
• Hospital discharge due to unstable angina pectoris (>2 months prior to enrollment)
• History of stroke (>2 months prior to enrollment)
• Peripheral occlusive arterial disease 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: preserved EF (Left ventricular ejection fraction (LVEF) >40%) and elevated NT-proBNP (>300 pg/ml; >900 pg/ml for patients with atrial fibrillation)
• 1245.121: reduced EF (LVEF =40%) and elevated NT-proBNP (=2500 pg/ml if EF 36 to 40%, =1000 pg/ml if EF 31 to 35%, =600 pg/ml if EF =30% or if EF =40% with documented hospitalisation for HF within 12 months prior to screening; for patients with atrial fibrillation, double the level of NT-proBNP is applied for each EF category)
• 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
• Uncontrolled hyperglycemia: fasting plasma glucose >240 mg/dl
• Severe renal impairment defined as eGFR <30 ml/min by Modification of diet in renal disease (MDRD) formula
• Intake of an investigational drug in another trial within 30 days prior to intake of study medication in this trial, or participating in another trial (involving an investigational drug and/or follow-up) Exclusion criteria for 1245.110 and 1245.121
• Myocardial infarction, coronary artery bypass graft surgery or other major cardiovascular surgery, stroke or transient ischaemic attack =90 days before screening
• Heart transplant recipient, or listed for heart transplant
• Acute decompensated HF
• Systolic blood pressure (SBP) =180 mmHg at randomisation
• Symptomatic hypotension and/or SBP <100 mmHg at screening or randomisation
• Impaired renal function defined as Estimated glomerular filtration rate (eGFR) Chronic Kidney Disease Epidemiology Collaboration Equation (based on serum creatinine value) <20 ml/min/1.73 m2 or requiring dialysis at screening

Related Conditions & MeSH terms

• Diabetes Mellitus, Type 2

Intervention

Drug:
• Placebo
Placebo
• Empagliflozin
Empagliflozin once daily

Locations

Country	Name	City	State
Germany	Boehringer Ingelheim	Ingelheim am Rhein

Sponsors (1)

Lead Sponsor	Collaborator
Boehringer Ingelheim

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	From first to last dose of study medication plus 7 days to account for the residual drug effect, up to 1639 days.
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.	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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