This study has been transitioned to CTIS with ID 2023-507846-96-00 check the CTIS register for the current data. The main reason for conducting this study is to help in answering the following research question:• How tirzepatide compares to…
ID
Source
Brief title
Condition
- Diabetic complications
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Time to first occurrence of a component event of a MACE-3.
Secondary outcome
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 revascularisation, hospitalisation 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:
- weight, BMI, and waist circumference
- HbA1c
- urinary albumin to creatinine ratio
- blood lipids: total cholesterol, HDL-cholesterol, LDL-cholesterol, and
triglycerides;
• Time to first occurrence of:
- coronary, carotid, or peripheral revascularisations, individually and as
composite
- hospitalisation due to unstable angina
- composite endpoint of new or worsening nephropath;
• Cumulative number of primary composite events of CV death and total (first
and recurrent) MI and/or stroke;
• Maximally tolerated tirzepatide dose will be measured based on:
• Incidence of TEAEs and permanent discontinuation of study drug due
to AEs
• Incidence of:
- pancreatitis
- severe gastrointestinal events
- any malignancy (including medullary and papillary thyroid cancers)
- severe hypoglycemic events
- Immune-mediated reactions including serious allergic and hypersensitivity
reactions
- hepatobiliary events (eg, acute cholecystitis, acute cholelithiasis and
drug-induced liver injury)
- acute renal failure or exacerbation of chronic renal failure
- diabetic retinopathy complications
- supraventricular arrhythmias and cardiac conduction disorders
• Mean change from baseline:
- blood pressure and pulse rate
- lipase
- pancreatic amylase
- calcitonin
- 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
- APPADL
- IW-SP
- 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.
Background summary
Tirzepatide is an investigational medicine called a dual agonist of
glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1
(GLP-1) receptors. It helps increase the release of insulin in the body, which
in turn lowers the levels of glucose in the body and its use could result in
substantial weight loss. GLP-1 receptor only agonists, such as dulaglutide,
have been shown to protect the cardiovascular system in the body, and to reduce
unwanted adverse cardiovascular events.
Tirzepatide could exceed the efficacy of most currently available type 2
diabetes medications in lowering glucose while possibly preventing
cardiovascular events in participants with type 2 diabetes. This study is
planned to compare tirzepatide to the currently available medication
dulaglutide and to evaluate the cardiovascular safety and protection of
tirzepatide in patients with type 2 diabetes.
Study objective
This study has been transitioned to CTIS with ID 2023-507846-96-00 check the CTIS register for the current data.
The main reason for conducting this study is to help in answering the following
research question:
• How tirzepatide compares to dulaglutide in preventing cardiovascular events
in participants with type 2 diabetes and a higher risk of cardiovascular events
(you may benefit from medications that either do not increase this risk or
prevent new serious cardiovascular complications).
Study design
SURPASS-CVOT is a Phase 3, event-driven, multi-centre, international,
randomised, double-blind, active comparator, parallel-group study. This study
will assess the effect of once weekly (QW) tirzepatide, on MACE-3, compared to
QW dulaglutide, when added to the standard of care (SoC) in patients with Type
2 Diabetes Mellitus (T2DM) with established Cardiovascular Disease (CVD) and
elevated risk for Major Adverse Cardiovascular Event (MACE).
In addition to study drug, all patients should receive standard of care for
their diabetes and CVD.
The study comparison is between tirzepatide and dulaglutide. Assignment to
tirzepatide or dulaglutide will be randomly allocated in a 1:1 ratio.
Randomisation will be stratified by country of enrolment and SGLT-2i use.
Tirzepatide will be administered once weekly with doses being escalated at
4-weekly intervals from the starting dose to a maximum dose defined in the
study protocol, or to the highest maintenance dose tolerated by the patient.
The dose of dulaglutide will be initiated and maintained at 1.5 mg QW. To
maintain blinding, a sham escalation of dulaglutide will be employed.
In order to reduce risk of hypoglycaemia, specific, individually tailored
adjustments of the respective anti-hyperglycaemic medications should be
considered during the entire study. At Visit 2, with the initiation of study
drug, dose adjustments to the concomitant glucose lowering medications will be
recommended per the protocol.
During the dose escalation period, if a telephone visit is deemed necessary to
support patient compliance, this is allowable at the discretion of the
investigator site personnel. Optional telephone visits can be performed
approximately 2 weeks after starting study drug and after each dose increase.
To optimise the number of patients who achieve the maximum escalation, both
tirzepatide and dulaglutide patients who do not reach the maximum escalation
during the initial dose escalation period will undergo a second dose escalation.
Patients will be followed for CV outcomes and other measures every 4 weeks for
the first 24 weeks and then followed approximately every 3 months thereafter.
The primary analysis of this study is an intention-to-treat (ITT) analysis;
therefore, every randomised patient will be followed until the patient*s *end-
of-follow-up,* regardless of compliance with study drug and adherence to study
visit schedule.
Approximately 12,500 patients will be enrolled at approximately 650 sites
globally.
Patients will be followed until at least 1615 patients experience a primary
endpoint event, centrally adjudicated as such. This is projected to occur after
an average of approximately 48 months of follow-up. The trial may be stopped
earlier on the basis of an Independent Data Monitoring Committee (IDMC) safety
review or for efficacy at the interim analysis.
A study duration of approximately 54 months is planned, but duration depends on
accrual of the requisite number of patients experiencing at least 1 component
of the primary endpoint. Consequently, additional visits may be required beyond
the planned duration. These additional visits, similar to visits during the
maintenance period, will occur every 3 months.
Approximately 3 months prior to the anticipated date of attaining 1615 events,
a study close-out period will be declared. During the study close-out period, a
final visit will be planned for each patient.
Intervention
Tirzepatide will be administered once weekly with doses being escalated at
4-weekly intervals from the starting dose to a maximum dose defined in the
study protocol, or to the highest maintenance dose tolerated by the patient.
The dose of dulaglutide will be initiated and maintained at 1.5 mg QW. To
maintain blinding, a sham escalation of dulaglutide will be employed.
Study burden and risks
The safety characteristics of tirzepatide are similar to that of dulaglutide.
The most common Adverse Events (AEs) were nausea, vomiting, and diarrhoea. In
general, these events are mild or moderate, with few severe events, and
transient. The highest previously tested tirzepatide dose was associated with
more gastro-intestinal (GI) AEs after a relatively short dose escalation
period. However, it is suggested that slower dose escalation and smaller dose
increments might improve tolerability.
Previous studies indicate that the potential risks/AEs with tirzepatide are
consistent with GLP-1 Receptor Agonists (RAs). The risks also include the
development of potential compound-specific anti-drug antibodies, similar to
other protein-based therapies. No apparent GIP RA effects have been identified
that would suggest additional or differential safety risks.
In clinical trials completed to date, dulaglutide has exhibited the expected
effect on insulin secretion and resulting in significant reductions in HbA1c.
Dulaglutide administration in patients with T2DM has been associated with
reductions in body weight. The most common AEs reported in patients
administered dulaglutide are those related to the GI organ class, including
nausea and vomiting
Various anti-hyperglycaemic background medications will be used throughout the
study. Some agents, like sulfonylureas (SUs) and insulins, may be associated
with occurrence of hypoglycaemia. This potential risk will be monitored
throughout the study and measures will be implemented to reduce the risk of
hypoglycaemia, including initial dose reduction and/or discontinuation of these
agents and frequent dose adjustment at the investigator*s discretion.
Normally patients with T2DM may visit their doctor once every three to six
months to monitor their disease. Doctors would normally ask questions to check
their physical, mental and nutritional health. They may perform a physical
exam, check their weight, blood pressure, and heart rate. The visits that are
involved in this study are more frequent and are in addition to these normal
health checks. However, patients may benefit from frequent expert medical care
for an approximately 54-month period.
There are risks that may be associated with the tests performed on the study
such as blood tests, ECGs, eye exams and from injection needle punctures from
administering the study drugs. Clinically routine monitoring and measures will
be implemented at the investigator*s discretion, to reduce the risk of these
occurring or to provide the appropriate care to patients that may experience
them.
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Eastgate Business Park, Little Island 11 Eastgate Road, Island House
Cork T45 KD39
IE
Listed location countries
Age
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 EITHER 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 (e.g.,
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.
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 hypoglycaemia and/or 1 or more events
of hypoglycaemia unawareness within 6 months prior to screening.
[11] Are currently planning treatment for diabetic retinopathy and/or macular
oedema.
[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 aetiology.
[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, or 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.
[37] Have had a blood transfusion or severe blood loss within 90 days prior to
screening or have known haematological conditions that may interfere with HbA1c
measurement.
[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.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2023-507846-96-00 |
| EudraCT | EUCTR2019-002735-28-NL |
| CCMO | NL72286.091.20 |