Diabetes Mellitus, Type 2NCT04937816

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

An observational study of Diabetes Mellitus, Type 2, run by Boehringer Ingelheim at 1 site in Germany.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

Who is it for?: Ages 18 years and older
Conditions the study is for: Diabetes Mellitus, Type 2
What is being tested?: Empagliflozin
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 16,746 participants
Where: 1 siteGermany
Study dates: 1 Jun 2021to 13 Jul 2021
Phase: Observational
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 years and older
All sexes
No healthy volunteers
Adult, Older adult

Study population: 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.

Who may be able to join

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

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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
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

Who cannot join

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)
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

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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

Trial locations and contacts

1 site in 1 country.

Germany1 site

Boehringer Ingelheim
Ingelheim, 55218

Other trials in Germany

About this study

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

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.

Conditions: Diabetes Mellitus, Type 2
Being tested: Placebo, Empagliflozin
Medical subject headings: Diabetes Mellitus, Type 2

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

PlaceboDrug
Placebo
EmpagliflozinDrug
Empagliflozin once daily

Study groups in NCT04937816
Study group	Role	What they receive
EMPA-REG - Placebo		Participants of the EMP-REG OUTCOME study (1245.25) who received placebo. Receives: Drug: 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). Receives: Drug: Empagliflozin
EMPA-REG - Empagliflozin high dose		Participants of the EMP-REG OUTCOME study (1245.25) who received a high dose of empagliflozin once daily (QD). Receives: Drug: Empagliflozin
EMPEROR-Preserved - Empagliflozin		Participants of the EMPEROR-Preserved study (1245.110) who received empagliflozin once daily (QD). Receives: Drug: Empagliflozin
EMPEROR-Preserved - Placebo		Participants of the EMPEROR-Preserved study (1245.110) who received placebo once daily (QD). Receives: Drug: Placebo
EMPEROR-Reduced - Empagliflozin		Participants of the EMPEROR-Reduced study (1245.121) who received empagliflozin once daily (QD). Receives: Drug: Empagliflozin
EMPEROR-Reduced - Placebo		Participants of the EMPEROR-Reduced study (1245.121) who received placebo once daily (QD). Receives: Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

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.
Measured: From first to last dose of study medication plus 7 days to account for the residual drug effect, up to 1639 days.

Secondary outcomes (1)

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.
Measured: From first to last dose of study medication plus 7 days to account for the residual drug effect, up to 1639 days.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

1 Jun 202113 Jul 2021

First posted24 Jun 2021
Study start1 Jun 2021
Primary completion13 Jul 2021
Study completion13 Jul 2021

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Other trials for Diabetes Mellitus, Type 2Studies of the same condition, open and under way.
More trials run by Boehringer IngelheimThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Observational
Observational model: Other
Time perspective: Retrospective
Enrolment: 16,746 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT04937816
Sponsor's protocol ID: 1245-0171
Status last verified: Jun 2023
First submitted: 21 Jun 2021
Last updated: 8 Feb 2024
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: No
FDA-regulated drug: Yes
FDA-regulated device: No
Individual data sharing: No: 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

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

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Study at a glance

From the registry record, last updated by the sponsor on 8 Feb 2024. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: A Meta-Analysis of Amputation Risk in Empagliflozin Studies (1245.25, 1245.110, 1245.121)
ClinicalTrials.gov ID: NCT04937816
Acronym / sponsor ID: 1245-0171
Conditions: Diabetes Mellitus, Type 2
Study type: Observational
Recruitment status: Completed
Enrolment: 16,746 participants (actual)
Lead sponsor: Boehringer IngelheimIndustry (pharma, biotech, devices)
Study start: 1 Jun 2021 (actual)
Primary completion: 13 Jul 2021 (actual)
Study completion: 13 Jul 2021 (actual)
First posted: 24 Jun 2021 (actual)
Results: Posted 8 Feb 2024

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Study design

Observational model: Other
Time perspective: Retrospective
Number of arms: 7

Arm	Type	Receives
EMPA-REG - Placebo	–	Drug: PlaceboParticipants of the EMP-REG OUTCOME study (1245.25) who received placebo.
EMPA-REG - Empagliflozin low dose	–	Drug: EmpagliflozinParticipants of the EMPA-REG OUTCOME study (1245.25) who received a low dose of empagliflozin once daily (QD).
EMPA-REG - Empagliflozin high dose	–	Drug: EmpagliflozinParticipants of the EMP-REG OUTCOME study (1245.25) who received a high dose of empagliflozin once daily (QD).
EMPEROR-Preserved - Empagliflozin	–	Drug: EmpagliflozinParticipants of the EMPEROR-Preserved study (1245.110) who received empagliflozin once daily (QD).
EMPEROR-Preserved - Placebo	–	Drug: PlaceboParticipants of the EMPEROR-Preserved study (1245.110) who received placebo once daily (QD).
EMPEROR-Reduced - Empagliflozin	–	Drug: EmpagliflozinParticipants of the EMPEROR-Reduced study (1245.121) who received empagliflozin once daily (QD).
EMPEROR-Reduced - Placebo	–	Drug: PlaceboParticipants of the EMPEROR-Reduced study (1245.121) who received placebo once daily (QD).

Who may qualify

Ages: 18 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult
Study population: 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.

Key inclusion criteria (20 listed)

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

Key exclusion criteria (9 listed)

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)
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

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
PlaceboPlacebo	Drug	EMPA-REG - Placebo, EMPEROR-Preserved - Placebo, EMPEROR-Reduced - Placebo
EmpagliflozinEmpagliflozin once daily	Drug	EMPA-REG - Empagliflozin high dose, EMPA-REG - Empagliflozin low dose, EMPEROR-Preserved - Empagliflozin, EMPEROR-Reduced - Empagliflozin

Primary outcome

Incidence Rate of Lower Limb Amputation (LLA)
Time frame: From first to last dose of study medication plus 7 days to account for the residual drug effect, up to 1639 days.
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.

1 secondary outcome

Incidence Rate of Adverse Events Related to Amputation
Time frame: From first to last dose of study medication plus 7 days to account for the residual drug effect, up to 1639 days.

Results and safety

Results posted to the registry on 8 Feb 2024, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Trial NCT01131676: Placebo	2,337	1,650
Trial NCT01131676: Empagliflozin 10 mg	2,347	1,790
Trial NCT01131676: Empagliflozin 25 mg	2,344	1,800
Trial NCT03057951: Placebo	2,991	2,046
Trial NCT03057951: Empagliflozin 10 mg	2,997	2,051
Trial NCT03057977: Placebo	1,867	1,352
Trial NCT03057977: Empagliflozin 10 mg	1,863	1,381

Primary outcome: Incidence Rate of Lower Limb Amputation (LLA)

Time frame: From first to last dose of study medication plus 7 days to account for the residual drug effect, up to 1639 days.. Number (95% Confidence Interval). Unit: Patients with events per 100pt-yrs

Measure	SAF-M1 Placebo n = 7185	SAF-M1 Empagliflozin n = 9546	SAF-M2 Placebo n = 4852	SAF-M2 Empagliflozin 10 mg n = 4859	Trial NCT01131676: Placebo n = 2333	Trial NCT01131676: Empagliflozin 10 mg or 25 mg n = 4687	Trial NCT03057951: Placebo n = 2989	Trial NCT03057951: Empagliflozin 10 mg n = 2996	Trial NCT03057977: Placebo n = 1863	Trial NCT03057977: Empagliflozin 10 mg n = 1863
Value	0.40 (0.30 to 0.52)	0.48 (0.39 to 0.58)	0.27 (0.17 to 0.39)	0.23 (0.13 to 0.34)	0.59 (0.41 to 0.81)	0.64 (0.51 to 0.79)	0.27 (0.15 to 0.42)	0.20 (0.10 to 0.33)	0.27 (0.10 to 0.52)	0.31 (0.12 to 0.58)

SAF-M1 Placebo vs SAF-M1 Empagliflozin: Hazard Ratio (HR): 1.02 (95% CI 0.73 to 1.42), p = 0.9276, Regression, Cox
SAF-M2 Placebo vs SAF-M2 Empagliflozin 10 mg: Hazard Ratio (HR): 0.85 (95% CI 0.45 to 1.60), p = 0.6205, Regression, Cox
Trial NCT01131676: Placebo vs Trial NCT01131676: Empagliflozin 10 mg or 25 mg: Hazard Ratio (HR): 1.09 (95% CI 0.73 to 1.63), p = 0.6768, Regression, Cox

Population analysed: 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).

1 secondary outcome is reported in the full results.

Adverse events

Other adverse events reported at 0% frequency or more

Group	Serious adverse events	Other adverse events
SAF-M1 Placebo	0 of 0	0 of 0
SAF-M1 Empagliflozin 10 mg	0 of 0	0 of 0
SAF-M1 Empagliflozin 25 mg	0 of 0	0 of 0
SAF-M2 Placebo	0 of 0	0 of 0
SAF-M2 Empagliflozin 10 mg	0 of 0	0 of 0
Trial NCT01131676: Placebo	0 of 0	0 of 0
Trial NCT01131676: Empagliflozin 10 mg	0 of 0	0 of 0
Trial NCT01131676: Empagliflozin 25 mg	0 of 0	0 of 0
Trial NCT03057977: Placebo	0 of 0	0 of 0
Trial NCT03057977: Empagliflozin 10 mg	0 of 0	0 of 0
Trial NCT03057951: Placebo	0 of 0	0 of 0
Trial NCT03057951: Empagliflozin 10 mg	0 of 0	0 of 0

Limitations and caveats (from the sponsor): 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.

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 8 Feb 2024.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Related InfoLink provided by the sponsor.
Individual participant dataSharing planned: No. 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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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

The record lists no contact. Use the official record to reach the sponsor.

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

An observational study of Diabetes Mellitus, Type 2, run by Boehringer Ingelheim at 1 site in Germany.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 20 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 8 Feb 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

Yes. Results are posted in the registry (first posted 8 Feb 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Incidence Rate of Lower Limb Amputation (LLA) (time frame: From first to last dose of study medication plus 7 days to account for the residual drug effect, up to 1639 days.). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04937816.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Feb 2024.