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Replication of the DECLARE Diabetes Trial in Healthcare Claims

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT04215523
Recruitment Status : Active, not recruiting
First Posted : January 2, 2020
Last Update Posted : January 2, 2020
Information provided by (Responsible Party):
Jessica Franklin, Brigham and Women's Hospital

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: Dapagliflozin Drug: DPP-4 inhibitor

Detailed Description:
This is a non-randomized, non-interventional study that is part of the RCT DUPLICATE initiative ( 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.

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Study Type : Observational
Actual Enrollment : 49790 participants
Observational Model: Cohort
Time Perspective: Retrospective
Official Title: Replication of the Dapagliflozin Effect on Cardiovascular Events (DECLARE)-TIMI 58 Diabetes Trial in Healthcare Claims
Actual Study Start Date : July 8, 2019
Estimated Primary Completion Date : September 22, 2020
Estimated Study Completion Date : September 22, 2020

Resource links provided by the National Library of Medicine

Group/Cohort Intervention/treatment
Exposure group
Drug: Dapagliflozin
Dapagliflozin dispensing claim is exposure

DPP-4 inhibitor
Reference group
Drug: DPP-4 inhibitor
DPP4 inhibitor dispensing claim is reference

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.

Information from the National Library of Medicine

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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 dapagliflozin 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 canagliflozin or a comparator drug (cohort entry date). Follow-up for the outcomes (a. 3P-MACE and b. composite of heart failure hospitalization/all-cause mortality), begins the day after drug initiation. As in the trial, patients are allowed to take other antidiabetic medications during the study.

Please see: for full code and algorithm definitions.

Eligible cohort entry dates:

Market availability of dapagliflozin in the U.S. started on January 8, 2014.

  • For Marketscan and Medicare: Jan 8, 2014-Dec 31, 2017 (end of data availability).
  • For Optum: Jan 8, 2014-Mar 31, 2019 (end of data availability).

Inclusion Criteria:

  1. Provision of informed consent prior to any study specific procedures (including run-in)
  2. Female or male aged ≥ 40 years
  3. Diagnosed with T2DM
  4. High Risk for CV event defined as having either established CV disease and/or multiple risk factors:

    - Established CV Disease (See Appendix E for details) OR No known cardiovascular disease AND at least two cardiovascular risk factors in addition to

    T2DM, defined as:

    • Age > 55 years in men and > 60 in women AND presence of at least 1 of the following additional risk factors (see Appendix E for details)
    • Dyslipidemia
    • Hypertension
    • Tobacco use
  5. WOCBP must take precautions to avoid pregnancy throughout the study and for 4 weeks after intake of the last dose.

    • WOCBP must have a negative urine pregnancy test. WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or is not postmenopausal.
    • WOCBP must be willing to use a medically accepted method of contraception that is considered reliable in the judgment of the Investigator. For inclusion in the optional genetic research, patients must fulfill the criterion specified in

Exclusion Criteria:

Patients should not meet any exclusion criteria at the time of randomization. If at the time of enrollment, it is known that the patient will not meet criteria after a successful run-in period he/she should not be entered into run in.

  1. Use of the following excluded medications:

    • Current or recent (within 24 months) treatment with pioglitazone and/or use of pioglitazone for 2 years or more at any time
    • Current or recent (within 12 months) treatment with rosiglitazone
    • Previous treatment with any SGLT2 inhibitor
    • Any patient currently receiving chronic (>30 consecutive days) treatment with an oral steroid at a dose equivalent to oral prednisolone ≥10 mg (e.g., betamethasone ≥1.2 mg, dexamethasone ≥1.5 mg, hydrocortisone ≥40 mg) per day
  2. Acute cardiovascular event [e.g., acute coronary syndrome (ACS), transient ischemic attack (TIA), stroke, any revascularization, decompensated HF, sustained tachycardia <8 weeks prior to randomization. Patients with acute cardiovascular events can be enrolled in the run-in period as long as randomization does not occur within 8 weeks of the event.
  3. Systolic BP >180 or diastolic BP >100 mmHg at randomization
  4. Diagnosis of Type 1 diabetes mellitus, MODY, or secondary diabetes mellitus
  5. History of bladder cancer or history of radiation therapy to the lower abdomen or pelvis at any time
  6. History of any other malignancy within 5 years (with the exception of successfully treated non-melanoma skin cancers)
  7. Chronic cystitis and/or recurrent urinary tract infections (3 or more in the last year)
  8. Any conditions that, in the opinion of the Investigator, may render the patient unable to complete the study including but not limited to cardiovascular (NYHA class IV CHF, recurrent ventricular arrhythmias) or non-cardiovascular disease (e.g., active malignancy with the exception of basal cell carcinoma, cirrhosis, chronic lung disease, severe autoimmune disease) and/or a likely fatal outcome within 5 years
  9. Pregnant or breast-feeding patients
  10. Involvement in the planning and/or conduct of the study or other dapagliflozin studies (applies to AZ, BMS, Hadassah and Thrombolysis in Myocardial Infarction [TIMI] or representative staff and/or staff at the study site)
  11. Previous randomization in the present study
  12. Active participation in another clinical study with IP and/or investigational device
  13. Individuals at risk for poor protocol or medication compliance during run-in period (reasonable compliance defined as 80 - 120%, unless a reason for non-compliance is judged acceptable by the Investigator). If for any reason, the Investigator believes that the patient will not tolerate or be compliant with IP or study procedures, the patient should not be randomized and considered a run-in failure. Patients will be excluded during run-in and should not be randomized if the following are observed from laboratory or observation during enrollment and run-in assessments:
  14. HbA1c ≥12% or HbA1c<6.5%
  15. AST or ALT >3x ULN or Total bilirubin >2.5 x ULN
  16. CrCl < 60 ml/min (based on the Cockroft-Gault equation)
  17. Hematuria (confirmed by microscopy at Visit 1) with no explanation as judged by the Investigator up to randomization. If bladder cancer is identified, patients are not eligible to participate.
  18. Any reason the Investigator believes the patient is not likely to be compliant with the study medication and protocol.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT04215523

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United States, Massachusetts
Brigham & Women's Hospital
Boston, Massachusetts, United States, 02120
Sponsors and Collaborators
Brigham and Women's Hospital
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Principal Investigator: Jessica Franklin, PhD Brigham and Womens
  Study Documents (Full-Text)

Documents provided by Jessica Franklin, Brigham and Women's Hospital:
Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: Jessica Franklin, Assistant Professor and Biostatician, Brigham and Women's Hospital Identifier: NCT04215523    
First Posted: January 2, 2020    Key Record Dates
Last Update Posted: January 2, 2020
Last Verified: December 2019

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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
Additional relevant MeSH terms:
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Diabetes Mellitus
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Dipeptidyl-Peptidase IV Inhibitors
Sodium-Glucose Transporter 2 Inhibitors
Molecular Mechanisms of Pharmacological Action
Hypoglycemic Agents
Physiological Effects of Drugs
Protease Inhibitors
Enzyme Inhibitors