Clinical trial NCT03936049: Replication of the LEADER Diabetes Trial in Healthcare Claims
Official title: Replication of the LEADER Diabetes Trial in Healthcare Claims
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Diabetes
Lead sponsor: Brigham and Women's Hospital
Sponsor class: OTHER
First posted: 2019-05-03
Enrollment: 168690
Sex: ALL
Minimum age (years): 50
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: RETROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: This study will involve a new user, parallel group, cohort study design comparing liraglutide to the DPP4 inhibitor (DPP4i) antidiabetic class as a proxy for placebo. Both 2nd generation sulfonylureas (SUs) and DPP4is are not known to have an impact on the outcome of interest. The comparison against DPP4i is the primary comparison. Initiators of 2nd generation SUs are used as a secondary comparator group. The patients will be required to have continuous enrollment during the baseline period of 180 days before initiation of liraglutide 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.

Brief 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.

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.

Eligibility criteria: Please see: https://drive.google.com/drive/folders/1WD618wrywYjEaXzfLTcuK-VCcnb6b-gV for full code and algorithm definitions.

Eligible cohort entry dates Market availability of liraglutide in the U.S. started on January 20, 2010. For Marketscan and Medicare: January 20, 2010-Dec 31, 2016 (end of data availability).

For Optum: January 20, 2010-Sep 30, 2017 (end of data availability).

Inclusion Criteria:

* Men or women with type 2 diabetes
* Either of the following:

  * Prior cardiovascular disease cohort: Age ≥ 50 years at screening, AND at least one of the following:

    * Prior MI
    * Prior stroke or TIA
    * Prior coronary, carotid or peripheral arterial revascularization
  * \>50% stenosis of coronary, carotid, or lower extremity arteries coded by Peripheral vascular disease
  * Chronic heart failure NYHA class II-III
  * CKD stage 3-6 as Chronic renal failure:
* No Prior cardiovascular disease group: Age ≥ 60 years at screening, AND at least one of the following:

  * Microalbuminuria or proteinuria
  * Hypertension and left ventricular hypertrophy by ECG or imaging
  * Ankle-brachial index \<0.9

Exclusion Criteria:

* Type 1 diabetes
* Use of a GLP-1 receptor agonist (exenatide, liraglutide or other) or pramlintide or any (dipeptidyl peptidase 4 (DPP-4) inhibitor within the 3 months prior to screening
* Use of long-term insulin in 90 days prior
* Diabetic ketoacidosis in 3 months prior to index date as Acute decompensation of glycaemic control requiring immediate intensification of treatment to prevent acute complications of diabetes (e.g., diabetic ketoacidosis) in the previous 3 months
* Inpatient (hospitalization) code for MI, stroke, revascularization, PTCA, CABG IN PRIOR 14 DAYS as An acute coronary or cerebrovascular event in the previous 14 days
* inpatient Heart failure (CHF) as Chronic heart failure NYHA class IV
* ESRD codes as Current continuous renal replacement therapy
* Liver disease as "End stage liver disease, defined as the presence of acute or chronic liver disease and recent history of one or more of the following: ascites, encephalopathy, variceal bleeding, bilirubin ≥ 2.0 mg/dL, albumin level ≤ 3.5 g/dL, prothrombin time ≥ 4 seconds prolonged, international normalised ratio (INR) ≥1.7 or prior liver transplant"
* Organ transplant codes as A prior solid organ transplant or awaiting solid organ transplant
* History of malignant neoplasm in previous 5 years 140.xx-208.xx (except 173.xx, non-melanoma skin cancer)
* Family or personal history of multiple endocrine neoplasia type 2 (MEN2) or familial medullary thyroid carcinoma (FMTC)
* Personal history of non-familial medullary thyroid carcinoma
* Drug abuse or dependence as Known use of non prescribed narcotics or illicit drugs
* Encounter for contraceptive management, Oral contraceptives, and pregnancy as "Females of childbearing potential who are pregnant, breast-feeding or intend to become pregnant or are not using adequate contraceptive methods (adequate contraceptive measures as required by local law or practice)"

Primary outcomes:
measure: Relative hazard of composite outcome of Stroke, MI, and Mortality
timeFrame: Through study completion (a median of 154-188 days)
Secondary outcomes:
Other outcomes:
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:
citation: 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.