| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Hormonal diseases [C19] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10045242 |
| E.1.2 | Term | Type II diabetes mellitus |
| E.1.2 | System Organ Class | 100000004861 |
|
| 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 |
To assess efficacy of maximally tolerated tirzepatide dose up to 15 mg QW compared to QW dulaglutide 1.5 mg on time to first occurrence of the composite endpoint of death from CV causes, MI, or stroke (MACE-3) when both are added to standard of care in patients with T2DM and high CV risk.
Primary analysis will be an assessment of NI of tirzepatide to dulaglutide for MACE-3. After establishing NI, superiority of tirzepatide compared to dulaglutide for MACE-3 will be evaluated.
|
|
| E.2.2 | Secondary objectives of the trial |
| To assess the superiority of tirzepatide up to 15 mg QW compared to dulaglutide 1.5 mg QW for time to death due to any cause, time to CV death, time to first occurrence of MI and time to first occurrence of stroke. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Addendum (7) - 15Dec2020 : The aim of this sub-study is to investigate
the diabetic retinopathy progression on tirzepatide based on systematic,
repeated collection and analyses of retinopathy images and to evaluate
these changes when compared to dulaglutide. |
|
| E.3 | Principal inclusion criteria |
[1] Men or women at least 40 years old with a diagnosis of T2DM (WHO
2019).
[2] Established CVD, including at least 1 of the following (a-c):
a. Coronary artery disease (CAD) with ANY of the following:
- Documented history of spontaneous MI
- ≥50% stenosis in 1 or more major coronary arteries, determined by
invasive angiography
- ≥50% stenosis in 2 or more major coronary arteries, determined by
computed tomography coronary angiography (CTCA), or
- History of surgical or percutaneous coronary revascularization
procedure;
b. Cerebrovascular disease – ANY of the following:
- Documented history of ischemic stroke
- Carotid arterial disease with ≥50% stenosis, documented by carotid
ultrasound, magnetic resonance imaging (MRI), or angiography
- Carotid stenting or surgical revascularization;
c. Peripheral arterial disease with EITHER of the following:
- Intermittent claudication and ankle-brachial index <0.9
- Prior nontraumatic amputation or peripheral vascular procedure (eg,
stenting or surgical revascularization), due to peripheral arterial
ischemia.
[3] HbA1c ≥7% (≥53 mmol/mol) and ≤10.5% (≤91.3 mmol/mol) based
on central laboratory assessment at screening.
[4] Body mass index (BMI) ≥25 kg/m2.
[5] At the time of signing the informed consent: Contraceptive use by
men or women should be consistent with local regulations regarding the
methods of contraception for those participating in clinical trials.
[6] In the investigator's opinion, patients are well motivated, capable,
and willing to learn how to self-inject treatment (tirzepatide or
dulaglutide), as required for this protocol (visually impaired persons
and/or persons with physical limitations who are not able to perform the
injections must have the assistance of an individual trained to inject the
study drug).
[7] Patients are capable of giving signed informed consent. |
|
| E.4 | Principal exclusion criteria |
[8] Have type 1 diabetes mellitus.
[9] Have uncontrolled diabetes requiring immediate therapy (such as diabetic ketoacidosis) at screening or randomization, in the judgment of the physician.
[10] Have had 1 or more events of severe hypoglycemia and/or 1 or more events of hypoglycemia unawareness within 6 months prior to screening.
[11] Are currently planning treatment for diabetic retinopathy and/or
macular edema.
[12] Have been hospitalized for CHF within 2 months prior to screening.
[13] Have chronic New York Heart Association Functional Classification IV CHF.
[14] Are currently planning a coronary, carotid, or peripheral artery revascularization.
[15] Had chronic or acute pancreatitis any time prior to screening, irrespective of etiology.
[16] Have a known clinically significant gastric emptying abnormality
such as severe gastroparesis or gastric outlet obstruction or have
undergone or currently planning any gastric bypass (bariatric) surgery
or restrictive bariatric surgery.
[17] Have acute or chronic hepatitis, signs or symptoms of any other liver disease, an alanine aminotransferase (ALT) level ≥3X the upper limit of normal (ULN) for the reference range, as determined by the central laboratory.
[18] Have known chronic severe renal failure (defined as a known eGFR <15 mL/minute/1.73 m2) or are on chronic dialysis.
[19] Have evidence of a significant, uncontrolled endocrine abnormality (eg, thyrotoxicosis or adrenal crises).
[20] Have a family or personal history of multiple endocrine neoplasia type 2 (MEN2) or familial medullary thyroid carcinoma (MTC) or personal history of nonfamilial MTC.
[21] Have a serum calcitonin level at screening of: (based on central laboratory results)
- ≥20 ng/L at Visit 1, if eGFR ≥60 mL/min/1.73 m2, or
- ≥35 ng/L at Visit 1, if eGFR <60 mL/min/1.73 m2.
[22] Have a history of an active or untreated malignancy or are in remission from a clinically significant malignancy for less than 5 years. An exception for this criterion is basal or squamous cell skin cancer, in situ carcinomas of the cervix, or in situ prostate cancer.
[23] Have a history of any other condition (such as known drug or alcohol abuse or psychiatric disorder) that, in the opinion of the investigator, may preclude the patient from following and completing the protocol.
[24] Have had a transplanted organ (corneal transplants [keratoplasty] allowed) or awaiting an organ transplant.
[25] Have any other condition (eg, hypersensitivity) that is a contraindication to any incretin or GLP-1 RAs.
[26] Have had an MI, percutaneous coronary revascularization
procedure, ischemic stroke, carotid stenting or surgical
revascularization, nontraumatic amputation or peripheral vascular
procedure (eg, stenting or surgical revascularization) less than 60 days
prior to screening.
[27] Have had coronary artery bypass graft surgery less than 5 years prior to Screening.
[28] Treatment with GLP-1 RA, or pramlintide in a period of 3 months
prior to Visit 1.
[29] Discontinuation of GLP-1 RA, or pramlintide due to intolerability any
time prior to Visit 1.
[30] Exclusion Criterion [30] has been deleted.
[31] Are currently enrolled in any other clinical study involving an investigational product or any other type of medical research judged not to be scientifically or medically compatible with this study.
[32] Have participated within the last 30 days in a clinical trial involving an investigational product. If the previous investigational product has a long half-life, 3 months or 5 half-lives (whichever is longer) should have passed.
[33] Have previously completed or withdrawn from this study or
randomized into any other study investigating tirzepatide.
[36] Any women who are pregnant or breastfeeding.
[37] Have had a blood transfusion or severe blood loss within 90 days
prior to screening or have known hematological conditions that may
interfere with HbA1c measurement.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Time to first occurrence of a component event of a MACE-3.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
An independent CEC will adjudicate all primary endpoint events.
The primary endpoint is the time from randomization to first occurrence of CEC-confirmed CV death, MI, or stroke.
Patients will be followed until approximately 1615 patients experience at least 1 component of the primary composite endpoint of CV death, MI, or stroke. |
|
| E.5.2 | Secondary end point(s) |
Key Secondary efficacy measures are:
• Time to death due to any cause;
• Time to CV death;
• Time to first occurrence of MI;
• Time to first occurrence of stroke.
• Time to first occurrence of the expanded composite CV outcome,
defined as either CV death, MI, stroke, coronary revascularization,
hospitalization for unstable angina
• Cumulative number of CV deaths and total (first and recurrent) HF
events requiring hospitalization and/or urgent HF visits
Additional secondary measures are:
• Proportion of patients with more than 10% weight loss from screening
after 36 months;
• Change from baseline in:
o weight, BMI, and waist circumference
o HbA1c
o urinary albumin to creatinine ratio
o blood lipids: total cholesterol, HDL-cholesterol, LDL-cholesterol, and
triglycerides;
• Time to first occurrence of:
o coronary, carotid, or peripheral revascularizations, individually and
as composite
o hospitalization due to unstable angina
o composite endpoint of new or worsening nephropathy
• Cumulative number of primary composite events of CV death and total
(first and recurrent) MI and/or stroke;
• Cumulative number of CV deaths and total (first and recurrent) HF
events requiring hospitalization and/or urgent HF visits.
Maximally tolerated tirzepatide dose will be measured based on:
• Incidence of TEAEs and permanent discontinuation of study drug due
to AEs
• Incidence of:
o pancreatitis
o severe gastrointestinal events
o any malignancy (including medullary and papillary thyroid cancers)
o severe hypoglycemic events
o immune-mediated reactions including serious allergic and
hypersensitivity reactions
o hepatobiliary events (eg, acute cholecystitis, acute cholelithiasis and
drug-induced liver injury)
o acute renal failure or exacerbation of chronic renal failure
o diabetic retinopathy complications
o supraventricular arrhythmias and cardiac conduction disorders
• Mean change from baseline:
o blood pressure
o pulse rate
o lipase
o pancreatic amylase
o calcitonin
o eGFR.
The effects of add-on therapy with up to 15 mg tirzepatide compared to
dulaglutide 1.5 mg will be measured based on:
• Change of antihyperglycemic drugs
• Patient-reported outcome
o APPADL
o IW-SP
o EQ-5D-5L
• Time to initiation of insulin of more than 3 months duration for those
patients not treated with insulin at study start
• eGFR from Cystatin-C. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary outcomes include various glycemic, body weight/composition, renal, biochemical, and health outcome endpoints relevant to the study population.
|
|
| 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 | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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 | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| 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 | 49 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 241 |
| 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 |
| Ukraine |
| Taiwan |
| Australia |
| Austria |
| Belgium |
| Brazil |
| Canada |
| China |
| Czechia |
| France |
| Germany |
| Greece |
| Hungary |
| India |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Mexico |
| Netherlands |
| Poland |
| Romania |
| Russian Federation |
| Slovakia |
| Spain |
| Sweden |
| Turkey |
| 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
|
| End of the study is the date of the last visit or last scheduled procedure shown in the protocol for the last patient. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 20 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 14 |
Print
