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

Replication of the CANVAS 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: Canagliflozin Drug: DPP-4 inhibitor

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
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Study Type : Observational
Actual Enrollment : 152202 participants
Observational Model: Cohort
Time Perspective: Retrospective
Official Title: Replication of Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes (CANVAS Trial)
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
DPP4i
Reference group
 Drug: DPP-4 inhibitor
DPP4 inhibitor dispensing claim is reference
Canagliflozin
Exposure group
 Drug: Canagliflozin
Canagliflozin dispensing claim is exposure
Outcome Measures
Primary Outcome Measures :
  1. Relative hazard of composite outcome of Stroke, MI, and Mortality [ Time Frame: Through study completion (a median of 120-140 days) ]
    Relative hazard of composite outcome of MI, stroke, and mortality - Please refer to uploaded protocol for full definition due to size limitations.


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
This study will involve a new user, parallel group, cohort study design comparing canagliflozin 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. Initiators of 2nd generation sulfonylureas 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 canagliflozin 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.
Criteria

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

Eligible cohort entry dates: 4/1/2013-12/31/2016 (market availability of sitagliptin in the U.S. started on 10/17/2006). For Optum, 4/1/2013-9/30/2017.

Inclusion Criteria:

  • Man or woman with a diagnosis of type 2 diabetes with glycated hemoglobin level ≥7.0% to≤10.5% at screening and be either

    1. not currently on antihyperglycemic agent (AHA) therapy or
    2. on AHA monotherapy or combination therapy with any approved class of agents: e.g., sulfonylurea, metformin, peroxisome proliferator-activated receptor gamma (PPARγ) agonist, alpha-glucosidase inhibitor, glucagon-like peptide-1 (GLP-1) analogue, dipeptidyl peptidase-4 (DPP-4) inhibitor, or insulin.
  • Age ≥30 years with documented symptomatic atherosclerotic cardiovascular disease
  • Age ≥50 years with 2 or more of the following risk factors determined at the screening visit

Exclusion Criteria:

  • History of diabetic ketoacidosis, type 1 diabetes, pancreas or beta-cell transplantation, or diabetes secondary to pancreatitis or pancreatectomy.
  • History of one or more severe hypoglycemic episode within 6 months before screening
  • Ongoing, inadequately controlled thyroid disorder.
  • Renal disease that required treatment with immunosuppressive therapy or a history of dialysis or renal transplant.
  • MI, unstable angina, revascularization procedure, or cerebrovascular accident within 3 months before screening, or a planned revascularization procedure, or history of New York Heart Association (NYHA) Class IV cardiac disease.
  • Findings on 12-lead electrocardiogram (ECG) that would require urgent diagnostic evaluation or intervention
  • History of hepatitis B surface antigen or hepatitis C antibody positive
  • Any history of or planned bariatric surgery.
  • History of malignancy within 5 years before screening
  • History of human immunodeficiency virus (HIV) antibody positive.
  • Subject has a current clinically important hematological disorder (e.g., symptomatic anemia, proliferative bone marrow disorder, thrombocytopenia).
  • Major surgery (i.e., requiring general anesthesia) within 3 months of the screening visit or any surgery planned during the subject's expected participation in the study
  • Current use of other sodium glucose co-transporter 2 (SGLT2) inhibitor.
  • Current use of a corticosteroid medication or immunosuppressive agent, or likely to require treatment with a corticosteroid medication
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 Stroke, MI, and Mortality [ Time Frame: Through study completion (a median of 120-140 days) ]
Relative hazard of composite outcome of 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 CANVAS Diabetes Trial in Healthcare Claims
Official Title Replication of Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes (CANVAS Trial)
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 canagliflozin 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. Initiators of 2nd generation sulfonylureas 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 canagliflozin 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.
Condition Diabetes
Intervention
  • Drug: Canagliflozin
    Canagliflozin dispensing claim is exposure
  • Drug: DPP-4 inhibitor
    DPP4 inhibitor dispensing claim is reference
Study Groups/Cohorts
  • DPP4i
    Reference group
    Intervention: Drug: DPP-4 inhibitor
  • Canagliflozin
    Exposure group
    Intervention: Drug: Canagliflozin
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) 		152202
Original Actual Enrollment
 (submitted: April 30, 2019) 		126154
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.

Eligible cohort entry dates: 4/1/2013-12/31/2016 (market availability of sitagliptin in the U.S. started on 10/17/2006). For Optum, 4/1/2013-9/30/2017.

Inclusion Criteria:

  • Man or woman with a diagnosis of type 2 diabetes with glycated hemoglobin level ≥7.0% to≤10.5% at screening and be either

    1. not currently on antihyperglycemic agent (AHA) therapy or
    2. on AHA monotherapy or combination therapy with any approved class of agents: e.g., sulfonylurea, metformin, peroxisome proliferator-activated receptor gamma (PPARγ) agonist, alpha-glucosidase inhibitor, glucagon-like peptide-1 (GLP-1) analogue, dipeptidyl peptidase-4 (DPP-4) inhibitor, or insulin.
  • Age ≥30 years with documented symptomatic atherosclerotic cardiovascular disease
  • Age ≥50 years with 2 or more of the following risk factors determined at the screening visit

Exclusion Criteria:

  • History of diabetic ketoacidosis, type 1 diabetes, pancreas or beta-cell transplantation, or diabetes secondary to pancreatitis or pancreatectomy.
  • History of one or more severe hypoglycemic episode within 6 months before screening
  • Ongoing, inadequately controlled thyroid disorder.
  • Renal disease that required treatment with immunosuppressive therapy or a history of dialysis or renal transplant.
  • MI, unstable angina, revascularization procedure, or cerebrovascular accident within 3 months before screening, or a planned revascularization procedure, or history of New York Heart Association (NYHA) Class IV cardiac disease.
  • Findings on 12-lead electrocardiogram (ECG) that would require urgent diagnostic evaluation or intervention
  • History of hepatitis B surface antigen or hepatitis C antibody positive
  • Any history of or planned bariatric surgery.
  • History of malignancy within 5 years before screening
  • History of human immunodeficiency virus (HIV) antibody positive.
  • Subject has a current clinically important hematological disorder (e.g., symptomatic anemia, proliferative bone marrow disorder, thrombocytopenia).
  • Major surgery (i.e., requiring general anesthesia) within 3 months of the screening visit or any surgery planned during the subject's expected participation in the study
  • Current use of other sodium glucose co-transporter 2 (SGLT2) inhibitor.
  • Current use of a corticosteroid medication or immunosuppressive agent, or likely to require treatment with a corticosteroid medication
Sex/Gender
Sexes Eligible for Study: All
Ages 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers No
Contacts Contact information is only displayed when the study is recruiting subjects
Listed Location Countries United States
Removed Location Countries  
 
Administrative Information
NCT Number NCT03936010
Other Study ID Numbers DUPLICATE-CANVAS
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: 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

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