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出境医 / 临床实验 / Replication of the TECOS Diabetes Trial in Healthcare Claims

Replication of the TECOS Diabetes Trial in Healthcare Claims

Study Description
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.

Condition or disease Intervention/treatment
Diabetes Drug: Sitagliptin Drug: Sulfonylurea

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
Layout table for study information
Study Type : Observational
Actual Enrollment : 349476 participants
Observational Model: Cohort
Time Perspective: Retrospective
Official Title: Replication of the TECOS Diabetes Trial in Healthcare Claims
Actual Study Start Date : September 22, 2017
Estimated Primary Completion Date : September 22, 2020
Estimated Study Completion Date : September 22, 2020
Arms and Interventions
Group/Cohort Intervention/treatment
2nd Generation SUs
Reference group
Drug: Sulfonylurea
2nd generation sulfonylurea dispensing claim is used as the reference

Sitagliptin
Exposure group
Drug: Sitagliptin
Sitagliptin dispensing claim is used as the exposure

Outcome Measures
Primary Outcome Measures :
  1. Relative hazard of composite outcome of ACS/unstable angina, Stroke, MI, and Mortality [ Time Frame: Through study completion (a median of 118 days) ]
    Relative hazard of composite outcome of ACS/unstable angina, MI, stroke, and mortality - Please refer to uploaded protocol for full definition due to size limitations.


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   50 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Sampling Method:   Non-Probability Sample
Study Population
This study will involve a new user, parallel group, cohort study design comparing sitagliptin to the 2nd generation sulfonylurea antidiabetic class as a proxy for placebo, since this class of antidiabetic drugs is not known to have an impact on the outcome of interest. The patients will be required to have continuous enrollment during the baseline period of 180 days before initiation of sitagliptin or a comparator drug (index date). Follow-up for the outcome (4P-MACE), begins the day after drug initiation. As in the trial, patients are allowed to take other antidiabetic medications during the study. Eligible cohort entry dates: 10/17/2006-12/31/2016 (market availability of sitagliptin in the U.S. started on 10/17/2006). For Optum, 10/17/2006-9/30/201.
Criteria

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

Inclusion Criteria:

  • Patients with a diagnosis of T2DM (ICD-9 Dx code of 250.x0 or 250.x2; ICD-10 Dx code of E11.x) in the 6 months prior to drug initiation
  • Metformin, pioglitazone, or a sulfonylurea (monotherapy or any dual combination) for each day in the prior 3 months
  • Any insulin use for each day in the prior 3 months
  • 2 outpatient visits
  • Patient is ≥50 years of age
  • History of a major clinical manifestation of coronary artery disease (i.e., MI, surgical or percutaneous [balloon and/or stent] coronary revascularization procedure
  • Ischemic cerebrovascular disease, including:

    • History of ischemic stroke. Strokes not known to be hemorrhagic will be allowed as part of this criterion;
    • Occlusion and stenosis of carotid artery without mention of cerebral infarction as History of carotid arterial disease as documented by ≥50% stenosis documented by carotid ultrasound, magnetic resonance imaging (MRI), or angiography, with or without symptoms of neurologic deficit
    • Peripheral arterial stenting or surgical revascularization, Lower extremity amputation, and Ankle brachial pressue index <0.9 as: Atherosclerotic peripheral arterial disease, as documented by objective evidence such as amputation due to vascular disease, current symptoms of intermittent claudication confirmed by an anklebrachial pressure index or toe brachial pressure index less than 0.9, or history of surgical or percutaneous revascularization procedure.
  • Encounter for contraceptive management and oral contraceptives as Female patients agree to use an effective method of contraception or must not otherwise be at risk of becoming pregnant.

Exclusion Criteria:

  • Patient has a history of type 1 diabetes mellitus or a history of ketoacidosis.
  • Patient has a history of ≥2 episodes of severe hypoglycemia during the 12 months prior to enrollment. Severe hypoglycemia (hypoglycemia requiring assistance) refers to instances in which the patient was sufficiently disoriented or incapacitated as to require help from another individual or from medical personnel (whether or not this assistance was actually provided).
  • Patient has taken an approved or investigational DPP-4 inhibitor agent (eg, sitagliptin, alogliptin, saxagliptin, or vildagliptin), GLP-1 analogues (eg, exenatide, exenatide LAR, or liraglutide), or a thiazolidinedione other than pioglitazone within the past 3 months.
  • Patient has cirrhosis of the liver, as assessed by medical history.
  • Pregnancy or planned pregnancy during the trial period.
  • Exclude patients with a combined comorbidity score >95th percentile as Patient has medical history that indicates a life expectancy of b2 years or might limit the individual's ability to take trial treatments for the duration of the study.
Contacts and Locations

Locations
Layout table for location information
United States, Massachusetts
Brigham & Women's Hospital
Boston, Massachusetts, United States, 02120
Sponsors and Collaborators
Brigham and Women's Hospital
Investigators
Layout table for investigator information
Principal Investigator: Jessica Franklin, PhD Brigham and Womens
Tracking Information
First Submitted Date April 29, 2019
First Posted Date May 3, 2019
Last Update Posted Date January 2, 2020
Actual Study Start Date September 22, 2017
Estimated Primary Completion Date September 22, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: April 30, 2019)
Relative hazard of composite outcome of ACS/unstable angina, Stroke, MI, and Mortality [ Time Frame: Through study completion (a median of 118 days) ]
Relative hazard of composite outcome of ACS/unstable angina, MI, stroke, and mortality - Please refer to uploaded protocol for full definition due to size limitations.
Original Primary Outcome Measures Same as current
Change History
Current Secondary Outcome Measures Not Provided
Original Secondary Outcome Measures Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title Replication of the TECOS Diabetes Trial in Healthcare Claims
Official Title Replication of the TECOS Diabetes Trial in Healthcare Claims
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.
Study Type Observational
Study Design Observational Model: Cohort
Time Perspective: Retrospective
Target Follow-Up Duration Not Provided
Biospecimen Not Provided
Sampling Method Non-Probability Sample
Study Population This study will involve a new user, parallel group, cohort study design comparing sitagliptin to the 2nd generation sulfonylurea antidiabetic class as a proxy for placebo, since this class of antidiabetic drugs is not known to have an impact on the outcome of interest. The patients will be required to have continuous enrollment during the baseline period of 180 days before initiation of sitagliptin or a comparator drug (index date). Follow-up for the outcome (4P-MACE), begins the day after drug initiation. As in the trial, patients are allowed to take other antidiabetic medications during the study. Eligible cohort entry dates: 10/17/2006-12/31/2016 (market availability of sitagliptin in the U.S. started on 10/17/2006). For Optum, 10/17/2006-9/30/201.
Condition Diabetes
Intervention
  • Drug: Sitagliptin
    Sitagliptin dispensing claim is used as the exposure
  • Drug: Sulfonylurea
    2nd generation sulfonylurea dispensing claim is used as the reference
Study Groups/Cohorts
  • 2nd Generation SUs
    Reference group
    Intervention: Drug: Sulfonylurea
  • Sitagliptin
    Exposure group
    Intervention: Drug: Sitagliptin
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Active, not recruiting
Actual Enrollment
 (submitted: December 30, 2019)
349476
Original Actual Enrollment
 (submitted: April 30, 2019)
287346
Estimated Study Completion Date September 22, 2020
Estimated Primary Completion Date September 22, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria

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

Inclusion Criteria:

  • Patients with a diagnosis of T2DM (ICD-9 Dx code of 250.x0 or 250.x2; ICD-10 Dx code of E11.x) in the 6 months prior to drug initiation
  • Metformin, pioglitazone, or a sulfonylurea (monotherapy or any dual combination) for each day in the prior 3 months
  • Any insulin use for each day in the prior 3 months
  • 2 outpatient visits
  • Patient is ≥50 years of age
  • History of a major clinical manifestation of coronary artery disease (i.e., MI, surgical or percutaneous [balloon and/or stent] coronary revascularization procedure
  • Ischemic cerebrovascular disease, including:

    • History of ischemic stroke. Strokes not known to be hemorrhagic will be allowed as part of this criterion;
    • Occlusion and stenosis of carotid artery without mention of cerebral infarction as History of carotid arterial disease as documented by ≥50% stenosis documented by carotid ultrasound, magnetic resonance imaging (MRI), or angiography, with or without symptoms of neurologic deficit
    • Peripheral arterial stenting or surgical revascularization, Lower extremity amputation, and Ankle brachial pressue index <0.9 as: Atherosclerotic peripheral arterial disease, as documented by objective evidence such as amputation due to vascular disease, current symptoms of intermittent claudication confirmed by an anklebrachial pressure index or toe brachial pressure index less than 0.9, or history of surgical or percutaneous revascularization procedure.
  • Encounter for contraceptive management and oral contraceptives as Female patients agree to use an effective method of contraception or must not otherwise be at risk of becoming pregnant.

Exclusion Criteria:

  • Patient has a history of type 1 diabetes mellitus or a history of ketoacidosis.
  • Patient has a history of ≥2 episodes of severe hypoglycemia during the 12 months prior to enrollment. Severe hypoglycemia (hypoglycemia requiring assistance) refers to instances in which the patient was sufficiently disoriented or incapacitated as to require help from another individual or from medical personnel (whether or not this assistance was actually provided).
  • Patient has taken an approved or investigational DPP-4 inhibitor agent (eg, sitagliptin, alogliptin, saxagliptin, or vildagliptin), GLP-1 analogues (eg, exenatide, exenatide LAR, or liraglutide), or a thiazolidinedione other than pioglitazone within the past 3 months.
  • Patient has cirrhosis of the liver, as assessed by medical history.
  • Pregnancy or planned pregnancy during the trial period.
  • Exclude patients with a combined comorbidity score >95th percentile as Patient has medical history that indicates a life expectancy of b2 years or might limit the individual's ability to take trial treatments for the duration of the study.
Sex/Gender
Sexes Eligible for Study: All
Ages 50 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers Not Provided
Contacts Contact information is only displayed when the study is recruiting subjects
Listed Location Countries United States
Removed Location Countries  
 
Administrative Information
NCT Number NCT03936062
Other Study ID Numbers DUPLICATE-TECOS
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement Not Provided
Responsible Party Jessica Franklin, Brigham and Women's Hospital
Study Sponsor Brigham and Women's Hospital
Collaborators Not Provided
Investigators
Principal Investigator: Jessica Franklin, PhD Brigham and Womens
PRS Account Brigham and Women's Hospital
Verification Date December 2019