Clinical trial NCT06659679: Emulating the PIONEER6 Diabetes Trial Using Healthcare Claims
Official title: Emulation of the Effects of Oral Semaglutide on Cardiovascular Outcomes in Individuals With Type 2 Diabetes: PIONEER6 Trial
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Diabetes Mellitus, Type 2
Lead sponsor: Brigham and Women's Hospital
Sponsor class: OTHER
First posted: 2024-10-26
Enrollment: 26126
Sex: ALL
Minimum age (years): 50
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: RETROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: The study population includes patients with Type 2 Diabetes (Type2DM), \>=50 years with established cardiovascular disease OR \>=60 years with subclinical cardiovascular disease.

Brief summary: Investigators are building an empirical evidence base for real world data through large-scale emulation 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 emulate, as closely as is possible in healthcare insurance claims data, the trial listed below/above. Although many features of the trial cannot be directly emulated 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 emulable 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 emulation for a range of possible reasons and does not provide information on the validity of the original RCT finding.

The PIONEER6 trial, is a is a non-inferiority trial to evaluate the effects of oral semaglutide versus placebo in terms of cardiovascular safety (CV death, nonfatal MI, or nonfatal stroke) in patients with type 2 diabetes.

The database study designed to emulate PIONEER6 will be a new-user active comparative study, where we compare the effect of oral semaglutide versus sitagliptin on MACE outcome among patients with T2DM. Sitagliptin was selected to act as an active-comparator proxy for placebo. Sitagliptin and the class of dipeptidyl peptidase-4 (DPP-4) inhibitors have been demonstrated not to have an effect on MACE in a series of RCTs, and they are used in similar stages of disease/line of therapy as semaglutide, as well as being similarly costly.

Eligibility criteria: Eligible cohort entry dates:

Market availability of oral semaglutide in the US began on 19th September 2019.

Optum: Study period between 20th Sept 2019 - 29th February 2024 Marketscan: Study period between 20th Sept 2019 - 31st Dec 2022 Medicare: Study period between 20th Sept 2019 - 31st Dec 2020

Inclusion Criteria:

* Type 2 diabetes mellitus
* Age above or equal to 50 years at screening and clinical evidence of cardiovascular disease: prior myocardial infarction, prior stroke or prior transient ischemic attack, prior coronary, carotid or peripheral arterial revascularization, more than 50% stenosis on angiography or imaging of coronary, carotid or lower extremities arteries, chronic heart failure - New York Heart Association (NYHA) class II-III, chronic renal impairment documents by estimated eGFR \<60ml/min/1.73 m2 per MDRD
* Age 60 years or older with subclinical evidence of cardiovascular disease. Subclinical cardiovascular risk factors as one of the following: persistent microalbuminuria (30-299mg/g) or proteinuria, ankle/brachial index less than 0.9

Exclusion Criteria:

* Type 1 diabetes mellitus, secondary or gestational diabetes
* Use of glucagon-like peptide-1 (GLP-1) receptor agonist (exenatide, liraglutide, or other) or pramlintide within 90 days prior to screening
* Use of any dipeptidyl peptidase 4 (DPP-IV) inhibitor within 30 days prior to screening
* History of diabetic ketoacidosis, chronic pancreatitis or idiopathic acute pancreatitis
* Any of the following: myocardial infarction, stroke, or hospitalization for unstable angina or transient ischemic attack within the past 60 days prior to screening
* Chronic heart failure New York Heart Association (NYHA) class IV
* Personal or family history of multiple endocrine neoplasia type 2 (MEN2) or familial medullary thyroid carcinoma
* Chronic hemodialysis or peritoneal dialysis
* End stage liver disease
* A prior solid organ transplant or awaiting solid organ transplant
* Diagnosis of malignant neoplasm in the previous 5 years
* Female of childbearing potential who is pregnant, breast-feeding or intends to become pregnant or is not using an adequate contraceptive method
* Proliferative retinopathy or maculopathy requiring treatment
* History of major surgical procedures involving the stomach potentially affecting absorption of trial product (e.g., subtotal and total gastrectomy, sleeve gastrectomy, gastric bypass surgery)
* Missing age or gender
* Nursing home admission

Primary outcomes:
measure: Major adverse cardiac event (MACE), including myocardial infarction, stroke, and all cause death
timeFrame: Through study completion (1 day after cohort entry date until the first of outcome or censoring)
Secondary outcomes:
Other outcomes:
measure: Cataract surgery (negative control)
timeFrame: Through study completion (1 day after cohort entry date until the first of outcome or censoring)
Locations:
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
Study officials:
affiliation: Brigham and Women's Hospital
name: Shirley Wang, PhD, ScM
role: PRINCIPAL_INVESTIGATOR
References: