DiabetesNCT04215536
Replication of the EMPAREG Diabetes Trial in Healthcare Claims
An observational study of Diabetes, run by Brigham and Women's Hospital at 1 site in United States.
Trial summary
Investigators are building an empirical evidence base for real world data through large-scale replication of randomized controlled trials. The investigators' goal is to understand for what types of clinical questions real world data analyses can be conducted with confidence and how to implement such studies. Read more about this study
- Who is it for?
- Ages 18 to 120 years
- Conditions the study is for
- Diabetes
- What is being tested?
- Empagliflozin and DPP-4 inhibitor
- How many people
- 103,752 participants
- Where
- 1 siteUnited States
- Study dates
- 8 Jul 2019to 18 Feb 2021
- Phase
- Observational
- Are there results?
- None posted in the registry
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 to 120 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: This study will involve a new user, parallel group, cohort study design comparing empagliflozin to the DPP-4 inhibitor (DPP4i) antidiabetic class. DPP4is serve as a proxy for placebo, since this class of antidiabetic drugs is not known to have an impact on the outcome of interest. The comparison against DPP4 inhibitors is the primary comparison. The patients will be required to have continuous enrollment during the baseline period of 180 days before initiation of empagliflozin or a comparator drug (cohort entry date). Follow-up for the outcome (3P-MACE), begins the day after drug initiation. As in the trial, patients are allowed to take other antidiabetic medications during the study.
Who may be able to join
- All of the following criteria needed to be met:
- Subjects with T2DM on a diet and exercise regimen who are drug-naïve (no anti-diabetes therapy for ≥12 weeks prior to randomization) or treated with any anti-diabetes therapy (except pioglitazone in Japan)
- Drug-naive patients were required to have HbA1c ≥7.0% (≥53 mmol/mol) and ≤9.0% (≤75 mmol/mol) at screening
- Pre-treated patients were required to have HbA1c ≥7.0% (≥53 mmol/mol) and ≤10.0 (≤86 mmol/mol) at screening
- Background anti-diabetes therapy had to be unchanged for ≥12 weeks prior to randomization
- If background anti-diabetes therapy included insulin, insulin dose had to be unchanged by >10% from the dose at randomization in the previous 12 weeks
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- Age ≥18 years (≥20 years in Japan and ≤65 years in India)
- Body mass index ≤45 kg/m2 at screening
- High risk of a cardiovascular event defined as ≥1 of the following:
- Confirmed history of myocardial infarction (>2 months prior to informed consent)
- Evidence of multivessel coronary artery disease (CAD), in ≥2 major coronary arteries or in the left main coronary artery, irrespective of revascularization status, i.e. one of the following:
- Presence of a significant stenosis (imaging evidence of ≥50% narrowing of the luminal diameter measured during a coronary angiography or a multi-sliced computed tomography [CT] angiography)
- Revascularization (percutaneous transluminal coronary angioplasty [PTCA] with or without stent, or coronary artery bypass grafting [CAGB]) ≥2 months prior to consent
- Combination of revascularization in one major coronary artery ≥2 months prior to consent (PCTA with or without stent, or CABG), and the presence of significant stenosis in another major coronary artery (imaging evidence of ≥50% narrowing of the luminal diameter measured during a coronary angiography or a multi-sliced CT angiography)
- Evidence of a single vessel CAD with the presence of significant stenosis i.e. imaging evidence of ≥50% narrowing of the luminal diameter of one major coronary artery in patients not subsequently successfully revascularized (measured during a coronary angiography or a multi-sliced CT angiography) and one or both of the following:
- -- A positive non-invasive stress test, confirmed by one of the following:
- Positive exercise tolerance test in subjects without a complete left bundle branch block, Wolff-Parkinson-White syndrome, or paced ventricular rhythm
- Positive stress echocardiography showing regional systolic wall motion abnormalities
- Positive scintigraphic test showing stress-induced ischemia, i.e. development of transient perfusion defects during myocardial perfusion imaging
- Patient discharged from hospital with a documented diagnosis of unstable angina within 12 months of consent
- Last episode of unstable angina >2 months prior informed consent with confirmed evidence of single- or multi-vessel CAD as defined above
- History of ischemic or haemorrhagic stroke (>2 months prior to informed consent)
- Presence of peripheral artery disease (symptomatic or asymptomatic ) documented by one of the following:
- Previous limb angioplasty, stenting, or bypass surgery
- Previous limb or foot amputation due to circulatory insufficiency; or angiographic evidence of significant (>50%) peripheral artery stenosis in at least one limb
- Evidence from a non-invasive measurement of significant (>50% or as reported as hemodynamically significant) peripheral artery stenosis in at least one limb
- Ankle brachial index of <0.9 in at least one limb
- Signed and dated written informed consent prior to screening in accordance with Good Clinical Practice and local legislation
Who cannot join
- Uncontrolled hyperglycemia with glucose >240 mg/dL (>13.3 mmol/L) after an overnight fast during placebo run-in and confirmed by a second measurement (not on the same day)
- Indication of liver disease, defined by serum levels of alanine amininotransferase, aspartate aminotransferase, or alkaline phosphatase above 3 x upper limit of normal (ULN) during screening or run-in phase
- Planned cardiac surgery or angioplasty within 3 months
- Estimated glomerular filtration rate <30 ml/min/1.73m2 (according to the Modification of Diet in Renal Disease equation) at screening or during run-in phase
- Bariatric surgery within the past two years and other gastrointestinal surgeries that induce chronic malabsorption
- Blood dyscrasias or any disorders causing hemolysis or unstable red blood cells e.g. malaria, babesiosis, hemolytic anemia)
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- Medical history of cancer (except for basal cell carcinoma) and/or treatment for cancer within the last 5 years
- Contraindications to background therapy according to the local label
- Treatment with anti-obesity drugs 3 months prior to informed consent or any other treatment at time of screening leading to unstable body weight (e.g. surgery, aggressive diet regimen, etc.)
- Treatment with systemic steroids at time of informed consent or change in dosage of thyroid hormones within 6 weeks prior to informed consent
- Any uncontrolled endocrine disorder except T2DM
- Pre-menopausal women (last menstruation ≤1 year prior to informed consent) who were nursing, pregnant, or of child-bearing potential and were not practicing an acceptable method of birth control, or did not plan to continue using this method throughout the study, or did not agree to submit to periodic pregnancy testing during the trial
- Acceptable methods of birth control include tubal ligation, transdermal patch, intrauterine devices/systems, oral, implantable or injectable contraceptives, sexual abstinence, double barrier method, vasectomy of partner
- Alcohol or drug abuse within 3 months of informed consent that would interfere with trial participation or any ongoing condition leading to decreased compliance with study procedures or study drug intake
- 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
- Any clinical condition that would jeopardize patient safety while participating in this clinical trial (in Canada, this included current genito-urinal infection or genito-urinal infection within 2 weeks prior to informed consent)
- Acute coronary syndrome, stroke, or transient ischemic attack within 2 months prior to informed consent
Trial locations and contacts
1 site in 1 country.
United States1 site
Brigham & Women's Hospital
Boston, Massachusetts, 02120
About this study
Official title: Replication of the EMPA-REG OUTCOME Diabetes Trial in Healthcare Claims
Investigators are building an empirical evidence base for real world data through large-scale replication of randomized controlled trials. The investigators' goal is to understand for what types of clinical questions real world data analyses can be conducted with confidence and how to implement such studies.
Read the detailed description
This is a non-randomized, non-interventional study that is part of the RCT DUPLICATE initiative (www.rctduplicate.org) of the Brigham and Women's Hospital, Harvard Medical School. It is intended to replicate, as closely as is possible in healthcare insurance claims data, the trial listed below/above. Although many features of the trial cannot be directly replicated in healthcare claims, key design features, including outcomes, exposures, and inclusion/exclusion criteria, were selected to proxy those features from the trial. Randomization is also not replicable in healthcare claims data but was proxied through a statistical balancing of measured covariates according to standard practice. Investigators assume that the RCT provides the reference standard treatment effect estimate and that failure to replicate RCT findings is indicative of the inadequacy of the healthcare claims data for replication for a range of possible reasons and does not provide information on the validity of the original RCT finding.
- Conditions
- Diabetes
- Being tested
- Empagliflozin, DPP-4 inhibitor
- Medical subject headings
- Diabetes Mellitus
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
EmpagliflozinDrug
Empagliflozin dispensing claim is exposure
DPP-4 inhibitorDrug
DPP4 inhibitor dispensing claim is reference
| Study group | Role | What they receive |
|---|---|---|
| DPP4i | Reference group Receives: Drug: DPP-4 inhibitor | |
| Empagliflozin | Exposure group Receives: Drug: Empagliflozin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Composite outcome of Stroke, MI, and Mortality
Composite outcome of MI, stroke, and mortality - Please refer to uploaded protocol for full definition due to size limitations.
Measured: Through study completion (a median of 120-140 days)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Jan 2020
- Study start8 Jul 2019
- Primary completion18 Feb 2021
- Study completion18 Feb 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for DiabetesStudies of the same condition, open and under way.
- More trials run by Brigham and Women's HospitalThe 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
- Cohort
- Time perspective
- Retrospective
- Enrolment
- 103,752 participants (actual)
Sponsor and investigators
- Lead sponsor
- Brigham and Women's Hospital
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Shirley Vichy Wang, Brigham and Women's Hospital
- Investigators
- Shirley Wang, PhD, ScM, Principal investigator, Brigham and Womens
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04215536
- Sponsor's protocol ID
- 2018P002966-DUP-EMPAREG
- Status last verified
- Jul 2023
- First submitted
- 30 Dec 2019
- Last updated
- 27 Jul 2023
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Publications
Franklin JM, Patorno E, Desai RJ, Glynn RJ, Martin D, Quinto K, Pawar A, Bessette LG, Lee H, Garry EM, Gautam N, Schneeweiss S. Emulating Randomized Clinical Trials With Nonrandomized Real-World Evidence Studies: First Results From the RCT DUPLICATE Initiative. Circulation. 2021 Mar 9;143(10):1002-1013. doi: 10.1161/CIRCULATIONAHA.120.051718. Epub 2020 Dec 17.
PubMed 33327727
Study at a glance
From the registry record, last updated by the sponsor on 27 Jul 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Replication of the EMPA-REG OUTCOME Diabetes Trial in Healthcare Claims
- ClinicalTrials.gov ID
- NCT04215536
- Acronym / sponsor ID
- 2018P002966-DUP-EMPAREG
- Conditions
- Diabetes
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 103,752 participants (actual)
- Lead sponsor
- Brigham and Women's HospitalUniversity, hospital or other
- Study start
- 8 Jul 2019 (actual)
- Primary completion
- 18 Feb 2021 (actual)
- Study completion
- 18 Feb 2021 (actual)
- First posted
- 2 Jan 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Investigators are building an empirical evidence base for real world data through large-scale replication of randomized controlled trials. The investigators' goal is to understand for what types of clinical questions real world data analyses can be conducted with confidence and how to implement such studies.
Detailed description
This is a non-randomized, non-interventional study that is part of the RCT DUPLICATE initiative (www.rctduplicate.org) of the Brigham and Women's Hospital, Harvard Medical School. It is intended to replicate, as closely as is possible in healthcare insurance claims data, the trial listed below/above. Although many features of the trial cannot be directly replicated in healthcare claims, key design features, including outcomes, exposures, and inclusion/exclusion criteria, were selected to proxy those features from the trial. Randomization is also not replicable in healthcare claims data but was proxied through a statistical balancing of measured covariates according to standard practice. Investigators assume that the RCT provides the reference standard treatment effect estimate and that failure to replicate RCT findings is indicative of the inadequacy of the healthcare claims data for replication for a range of possible reasons and does not provide information on the validity of the original RCT finding.
Study design
- Observational model
- Cohort
- Time perspective
- Retrospective
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| DPP4i | – | Drug: DPP-4 inhibitorReference group |
| Empagliflozin | – | Drug: EmpagliflozinExposure group |
Who may qualify
- Ages
- 18 to 120 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- This study will involve a new user, parallel group, cohort study design comparing empagliflozin to the DPP-4 inhibitor (DPP4i) antidiabetic class. DPP4is serve as a proxy for placebo, since this class of antidiabetic drugs is not known to have an impact on the outcome of interest. The comparison against DPP4 inhibitors is the primary comparison. The patients will be required to have continuous enrollment during the baseline period of 180 days before initiation of empagliflozin or a comparator drug (cohort entry date). Follow-up for the outcome (3P-MACE), begins the day after drug initiation. As in the trial, patients are allowed to take other antidiabetic medications during the study.
Key inclusion criteria (28 listed)
- Subjects with T2DM on a diet and exercise regimen who are drug-naïve (no anti-diabetes therapy for ≥12 weeks prior to randomization) or treated with any anti-diabetes therapy (except pioglitazone in Japan)
- Age ≥18 years (≥20 years in Japan and ≤65 years in India)
- Body mass index ≤45 kg/m2 at screening
- High risk of a cardiovascular event defined as ≥1 of the following:
Key exclusion criteria (17 listed)
- Uncontrolled hyperglycemia with glucose >240 mg/dL (>13.3 mmol/L) after an overnight fast during placebo run-in and confirmed by a second measurement (not on the same day)
- Indication of liver disease, defined by serum levels of alanine amininotransferase, aspartate aminotransferase, or alkaline phosphatase above 3 x upper limit of normal (ULN) during screening or run-in phase
- Planned cardiac surgery or angioplasty within 3 months
- Estimated glomerular filtration rate <30 ml/min/1.73m2 (according to the Modification of Diet in Renal Disease equation) at screening or during run-in phase
- Bariatric surgery within the past two years and other gastrointestinal surgeries that induce chronic malabsorption
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 |
|---|---|---|
| EmpagliflozinEmpagliflozin dispensing claim is exposure | Drug | Empagliflozin |
| DPP-4 inhibitorDPP4 inhibitor dispensing claim is reference | Drug | DPP4i |
Primary outcome
Composite outcome of Stroke, MI, and Mortality
Time frame: Through study completion (a median of 120-140 days)
Composite outcome of MI, stroke, and mortality - Please refer to uploaded protocol for full definition due to size limitations.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Jul 2023.
- Derived from this study: PubMed 33327727Franklin JM, Patorno E, Desai RJ, Glynn RJ, Martin D, Quinto K, Pawar A, Bessette LG, Lee H, Garry EM, Gautam N, Schneeweiss S. Emulating Randomized Clinical Trials With Nonrandomized Real-World Evidence Studies: First Results From the RCT DUPLICATE Initiative. Circulation. 2021 Mar 9;143(10):1002-1013. doi: 10.1161/CIRCULATIONAHA.120.051718. Epub 2020 Dec 17.
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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.
Shirley Wang, PhD, ScM principal investigator
Brigham and Womens
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, run by Brigham and Women's Hospital at 1 site in United States.
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 28 inclusion and 17 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 27 Jul 2023. 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 United States. 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?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
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?
Composite outcome of Stroke, MI, and Mortality (time frame: Through study completion (a median of 120-140 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 NCT04215536, which also lists 1 linked publication.
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 27 Jul 2023.