E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Cardiovascular events in patients with Type 2 diabetes |
|
E.1.1.1 | Medical condition in easily understood language |
Heart conditions in patients with Type 2 diabetes |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10012654 |
E.1.2 | Term | Diabetic complications cardiovascular |
E.1.2 | System Organ Class | 100000004860 |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The main objective is to test the hypothesis that once-weekly injection of 1.5-mg Dulaglutide reduces the occurrence of the composite primary endpoint of death from CV causes, nonfatal myocardial infarction
(MI), or nonfatal stroke when added to the glucose-lowering regimen of patients with type 2 diabetes, compared to
the addition of a once-weekly placebo injection. |
|
E.2.2 | Secondary objectives of the trial |
The secondary efficacy objectives are to assess the effects of add-on therapy with 1.5-mg Dulaglutide compared to placebo on the occurence of :
- all cause mortality
- each component of the composite primary endpoint
- heart failure (HF) requiring hospitalization or an urgent HF visit
- hospitalization for unstable angina
- the composite microvascular endpoint of diabetic retinopathy requiring laser therapy, vitrectomy, or anti-VEGF therapy, development of clinical proteinuria, a 30% decline in estimated glomerular filtration rate (eGFR), or need for chronic renal replacement therapy
The prespecified safety objectives are to assess the effects of add-on therapy with 1.5-mg Dulaglutide compared to placebo on the incidence of:
- acute pancreatitis
- any cancer (excluding basal and squamous cell skin cancer)
- medullary thyroid carcinoma (MTC)
- C-cell hyperplasia
- discontinuation of study drug for any reason
- severe hypoglycemia
- allergic/hypersensitivity reactions |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients are eligible to be included in the study only if they meet all of the following criteria:
[1] Men or women with type 2 diabetes based on:
a) a previous diagnosis of type 2 diabetes; or
b) newly detected type 2 diabetes based on the American Diabetes Association criteria (ADA 2011) as either two of the following criteria or one of the following criteria that is confirmed on a second day:
- fasting plasma glucose ≥7.0 mmol/L (126 mg/dL), or
- 2-hour plasma glucose ≥11.1 mmol/L (200 mg/dL) following a
75-gram oral glucose load, as described by the World Health
Organization (WHO 2006), or
- HbA1c ≥6.5% (≥48 mmol/mol)
[2] HbA1c value of ≤9.5% (≤81 mmol/mol) at screening
[3] Are taking:
a) no glucose-lowering drugs; OR
b) 1 or 2 classes of oral glucose-lowering drugs; with or without basal insulin daily [as defined below in (d)]; if one of the oral glucose-lowering drugs is a DPP-IV inhibitor, the patient must be willing to stop the DPP-IV inhibitor after eligibility is confirmed; OR
c) 1 or 2 classes of oral glucose-lowering drugs with a GLP-1 analog; with or without basal insulin daily [as defined below in (d)]; the patient must be willing to stop the GLP-1 analog after eligibility is confirmed; OR
d) basal insulin daily defined as 1 to 2 injections per day of either glargine, detemir, neutral protamine Hagedorn (NPH), or another approved basal insulin.
[4] No change in the number or class of glucose-lowering drugs, no change in excess of doubling or halving the dose of these drugs, and if on insulin, no change in the dose of insulin in excess of 20% of the average daily dose, for at least 3 months before screening
[5] If age ≥50 years and established clinical vascular disease defined as 1 or more of the following:
- a history of MI
- a history of ischemic stroke
- a history of coronary, carotid, or peripheral artery revascularization. If prior coronary artery bypass grafting (CABG), the CABG should have been performed >2 years prior to randomization. If prior carotid or
peripheral artery revascularization, the revascularization should have been performed >2 months prior to randomization.
- hospitalization for unstable angina with ECG changes (new or
worsening ST or T wave changes), or myocardial ischemia on
imaging, or need for percutaneous coronary intervention (PCI);
OR
- If age ≥55 years and subclinical vascular disease defined as 1 or more of the following:
- a history of myocardial ischemia by a stress test or with cardiac
imaging, with or without history of exertional angina
- >50% vascular stenosis with imaging of the coronary, carotid, or lower extremity arteries, with or without claudication history
- ankle-brachial index <0.9
- 2 consecutive values or a documented history of persistent eGFR<60 mL/minute/1.73m2
- a history of hypertension with documented LV hypertrophy on an ECG or echocardiogram
- documented history of persistent microalbuminuria, or macroalbuminuria; or 2 consecutive urine samples demonstrating micro- or macroalbuminuria
OR
- If age ≥60 years and at least 2 or more of the following risk factors for CV outcomes:
- current tobacco use (any form of tobacco)
- use of at least 1 approved lipid modifying therapy to treat hypercholesterolemia or a documented untreated low-density lipoprotein cholesterol (LDL-C) ≥3.4 mmol/L (130 mg/dL) within the past 6 months
- documented treated or untreated high-density lipoprotein cholesterol (HDL-C) <1.0 mmol/L (40 mg/dL) for men and <1.3 mmol/L (50 mg/dL) for women or triglycerides ≥2.3 mmol/L (200 mg/dL) within the past 6
months
- use of at least 1 blood pressure medication to treat hypertension or
untreated systolic blood pressure (SBP) ≥140 mm Hg or diastolic
blood pressure (DBP) ≥95 mmHg
- measured waist-to-hip ratio >1.0 for men and >0.8 for women
[6] Body mass index ≥23 kg/m2
[7] Adherence to study drug during the run-in period is 100%
[8] In the investigator’s opinion, are well-motivated, capable, and willing to selfinject study treatment once weekly, as required for this protocol
[9] Have given written informed consent to participate in this study in accordance
with local regulations and Ethical Review Board (ERB) governing the study
site |
|
E.4 | Principal exclusion criteria |
Patients will be excluded from the study if they meet any of the following criteria:
[1] Uncontrolled diabetes requiring immediate therapy (such as diabetic ketoacidosis) at screening or randomization, in the judgment of the physician.
[2] Have experienced a severe hypoglycemic episode within 1 year prior to randomization.
[3] Have experienced an acute coronary or cerebrovascular event within 2 months prior to randomization.
[4] Are currently planning a coronary, carotid, or peripheral artery
revascularization.
[5] Have known chronic renal failure (defined as a known eGFR
<15 mL/minute/1.73m2) or are on chronic dialysis at screening.
[6] Have a known clinically significant gastric emptying abnormality (for
example, severe diabetic gastroparesis or gastric outlet obstruction) or have undergone gastric bypass (such as bariatric) surgery.
[7] Have a past history of chronic, acute, or idiopathic pancreatitis or
signs/symptoms of pancreatitis.
[8] Have severe hepatic dysfunction such as portal hypertension or cirrhosis, acute or chronic hepatitis, signs or symptoms of any other liver disease, or an alanine transaminase (ALT) level ≥3.0 times the upper limit of normal (ULN) for the reference range at screening.
[9] Have a) any self or family history of medullary C-cell hyperplasia, focal hyperplasia, carcinoma (including sporadic, familial or part of multiple endocrine neoplasia MEN 2A or 2B syndrome), or
b) any known self or family history of type 2A or type 2B multiple endocrine neoplasia (MEN 2A or 2B) in the absence of known C-cell hyperplasia. This includes patients with a family history of MEN 2A or 2B whose family history for the syndrome is RET negative. The only exception for this exclusion will be patients whose family members with MEN 2A or 2B have a known RET mutation and the potential patient for the study is negative for that RET mutation.
[10] Have a calcitonin value ≥20 pg/mL according to the central laboratory measurement at screening.
[11] Are previous organ transplant recipients or are awaiting an organ transplant (corneal transplants [keratoplasty] are allowed).
[12] Are taking a weight loss drug (over-the-counter or prescription) and are unwilling or unable to discontinue the drug at the time of screening or are taking pramlintide at the time of screening.
[13] History of, an active, or untreated malignancy, in remission from a clinically significant malignancy (other than basal or squamous cell skin cancer, in situ carcinomas of the cervix, or in situ prostate cancer) for less than 5 years prior to, or are receiving or planning to receive therapy for cancer, at screening.
[14] Females who are pregnant or have a positive pregnancy test at screening, or who have given birth within the past 90 days, or who are breastfeeding.
[15] Females of childbearing potential (that is, females who are and who are between menarche and less than 1-year past the last menses with an intact uterus) who do not agree to use a reliable method of birth control during the study and for 1 month following the last dose of study drug. Menopause is the absence of menses for ≥1 year and/or surgically or chemically induced.
[16] Are medically unstable with life expectancy <1 year.
[17] Are unwilling to permit sites to contact their primary physicians to
communicate information about the study and the patient’s data.
[18] In the judgment of the investigator, have any other condition likely to limit protocol compliance or reporting of AEs (for example, conditions such as alcoholism, mental illness, drug dependence, or not having access to a refrigerator to store study drug).
[19] Are currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an investigational product or nonapproved use of a drug or device (other than the investigational product used in this study), or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study, or intend to participate in another clinical trial while participating in this study.
[20] Have previously completed or withdrawn from any study investigating dulaglutide.
[21] Are investigator site personnel directly affiliated with this study and/or their immediate families. Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted.
[22] Are Lilly employees or employees of the CRO involved in the study. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy measure is the time to first occurrence (after randomization) of the composite of death from CV causes, nonfatal MI, or nonfatal stroke. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Throughout the duration of the study |
|
E.5.2 | Secondary end point(s) |
Secondary efficacy measures include time (after randomization) to:
- first occurrence of the composite microvascular endpoint of diabetic retinopathy requiring laser therapy, vitrectomy or anti-VEGF therapy, development of clinical proteinuria, a 30% decline in estimated glomerular filtration rate (eGFR), or need for chronic renal replacement therapy
- first hospitalization for unstable angina
- first occurrence of each component of the composite primary endpoint
- death
-first occurrence of heart failure (HF) requiring hospitalization or an urgent HF visit |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Throughout the duration of the study |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
|
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 159 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Australia |
Brazil |
Bulgaria |
Canada |
Chile |
Colombia |
Czech Republic |
Germany |
Hungary |
India |
Korea, Democratic People's Republic of |
Latvia |
Lithuania |
Mexico |
New Zealand |
Poland |
Romania |
Russian Federation |
South Africa |
Spain |
Sweden |
Taiwan |
United Kingdom |
United States |
|
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 8 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 8 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 0 |