Objective: To demonstrate the non-inferiority of ertugliflozin compared with anon-ertugliflozin comparator group on the time to first occurrence of any of thecomponents of the composite endpoint of cardiovascular death, non-fatal…
Source
Brief title
Condition
- Diabetic complications
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary cardiovascular endpoint is time to first occurrence of any of the
components of the composite endpoint of:
- Cardiovascular death;
- Non-fatal myocardial infarction;
- Non-fatal stroke.
Secondary outcome
Time to first occurrence of any of the components of the composite endpoint of:
- Cardiovascular death;
- Non-fatal myocardial infarction;
- Non-fatal stroke;
- Hospitalization for unstable angina.
- Time to first occurrence of:
- Fatal or non-fatal myocardial infarction;
- Fatal or non-fatal stroke;
- Hospitalization for a primary diagnosis of heart failure;
- Individual components of the MACE plus (cardiovascular death, non-fatal
myocardial infarction, non-fatal stroke, hospitalization for unstable angina).
- All MACE plus events (ie, not censored at the time of the first event).
- All cause mortality.
Secondary non cardiovascular event (protocol-specific) objectives and endpoints
along with
primary and secondary objectives, hypotheses and endpoints for the insulin *
metformin and
SU monotherapy glycemic sub-studies are described in the body of the protocol in
Sections 2.2, 2.3, 2.4, 2.6, 2.7 and 2.8.
Background summary
Background and Rationale:
Ertugliflozin (MK-8835/PF-04971729) is a potent inhibitor of Sodium-Glucose
co-Transporter 2 (SGLT2) and possesses a high selectivity over glucose
transport via
Sodium-Glucose co-Transporter 1 (SGLT) and several other glucose transporters
(GLUT1-4). Ertugliflozin inhibits renal glucose reabsorption resulting in
urinary glucose
excretion and thereby reducing plasma glucose and HbA1c in subjects with type 2
diabetes
mellitus (T2DM). Ertugliflozin is being developed as an adjunct to diet and
exercise to
improve glycemic control in patients with T2DM.
Individuals with T2DM are 2 to 4 times more likely to die from cardiovascular
disease than
adults without diabetes1 and coronary heart disease and stroke account for
approximately
two-thirds of deaths in people with diabetes.2 Given the substantial
cardiovascular morbidity
and mortality from T2DM, an understanding of the cardiac safety of a new agent
for T2DM
is of paramount importance. The United States Food and Drug Administration
(FDA) has
revised its approval process and guidelines for all new anti-diabetic therapies
requiring that
acceptable levels of cardiovascular safety are demonstrated at the time of the
New Drug
Application (NDA) filing as well as post-approval.3 The European Medicines
Agency
(EMA) has also updated its guidelines requiring that sponsors of novel diabetes
agents
demonstrate that the new compound does not increase the risk of macrovascular
complications at the time of the Marketing Authorization Application (MAA).4
Both the
FDA and EMA guidance documents recommend that an assessment of cardiovascular
safety
needs to include subjects with T2DM and elevated cardiovascular risk.
This trial will contribute to a program-wide meta-analysis of cardiovascular
endpoints
occurring in the ertugliflozin Phase 2 and Phase 3 development program. This
meta-analysis
is intended to evaluate the cardiovascular safety of ertugliflozin to support
the regulatory
submission of ertugliflozin. The primary and secondary objectives for the
program-wide
cardiovascular meta-analysis are listed below.
Additionally, this trial includes a pre-defined glycemic sub-study in subjects
receiving
background insulin * metformin and another pre-defined sub-study in subjects
receiving
background sulfonylurea (SU) monotherapy. Details on the objectives and
endpoints for
these sub-studies are described in the body of the protocol in Sections 2.3,
2.4, 2.7 and 2.8.
Study objective
Objective:
To demonstrate the non-inferiority of ertugliflozin compared with a
non-ertugliflozin comparator group on the time to first occurrence of any of the
components of the composite endpoint of cardiovascular death, non-fatal
myocardial
infarction or non-fatal stroke.
Study design
Study Design:
This trial is a multicenter, randomized, double-blind, placebo-controlled,
event-driven trial
that includes a main cardiovascular study and two glycemic sub-studies (see
details below)
and it is designed to contribute to the total number of cardiovascular
endpoints from the
Phase 2 and Phase 3 ertugliflozin development program. These cardiovascular
endpoints
will be included in a program-wide meta-analysis to evaluate the cardiovascular
safety of
ertugliflozin compared with a non-ertugliflozin comparator group. Beyond the
effects on
cardiovascular endpoints, the trial is also designed to assess the safety and
tolerability of
ertugliflozin and its effects on measures of glycemic control, blood pressure,
body weight,
renal function and albuminuria. As mentioned above, this trial also includes a
pre-defined
glycemic sub-study in subjects receiving background insulin * metformin and
another
pre-defined glycemic sub-study in subjects receiving background SU monotherapy
(further
details on the sub-studies are provided in Sections 3.2 and 3.3 respectively).
Approximately
3900 subjects will be enrolled and the randomization ratio will be 1:1:1 to 5
mg ertugliflozin
once daily, 15 mg ertugliflozin once daily or placebo.
This trial will contribute to the program-wide meta-analysis of cardiovascular
endpoints
occurring in the ertugliflozin Phase 2 and Phase 3 development program as
follows.
First, at the time of the NDA submission, the cardiovascular endpoints from
this trial will be
combined with the cardiovascular endpoints from the rest of the Phase 2 and 3
development
program to enable a meta-analysis to support the cardiovascular safety of
ertugliflozin. The
endpoint for the meta-analysis will be: time to first occurrence of any of the
components of
the composite endpoint of cardiovascular death, non-fatal myocardial
infarction, non-fatal
stroke, or hospitalization for unstable angina. This endpoint will also be
referred to as
MACE plus. The goal of this meta-analysis will be to rule out a hazard ratio of
1.8 (an
80% increase in the risk of MACE plus relative to a non-ertugliflozin
comparator group).
Second, if applicable, the trial may continue in the post-approval period in
order to rule out a
hazard ratio of 1.3 (a 30% increase in the risk of MACE relative to a
non-ertugliflozin
comparator group) via meta-analysis for the primary endpoint of: time to the
first occurrence
any of the components of the composite endpoint of cardiovascular death,
non-fatal
myocardial infarction, or non-fatal stroke. This endpoint will also be referred
to as MACE.
At the end of the trial, if non-inferiority at the 1.3 margin is established
for the primary
MACE endpoint for the ertugliflozin development program, then a test of
superiority on this
endpoint will be performed.
Intervention
Subjects will be randomized in a 1:1:1 ratio to receive ertugliflozin 5 mg,
ertugliflozin,15 mg ertugliflozin or matching placebo once daily added to their
background therapy. The randomization will be stratified by sub-study and by
geographic region (within sub-study). The stratification factor for sub-study
will have four levels: subjects entering the insulin metformin sub-study on a
background of insulin alone, subjects entering the insulin metformin sub-study
on a background of insulin plus metformin, subjects entering the SU monotherapy
sub-study, and subjects entering the main cardiovascular study but not any of
the sub-studies.
Study burden and risks
Several SGLT2 inhibitors are in clinical development and as of August 2013, one
SGLT2
inhibitor is approved in the U.S. (canagliflozin) and another (dapagliflozin)
is approved in
the European Union. Based on available clinical trial data with dapagliflozin
and
canagliflozin, several potential risks from SGLT2 inhibition have been
identified. In clinical
trials, the rate of genital fungal infections in males and females has
consistently been higher
in subjects receiving SGLT2 inhibitors as compared to placebo or other diabetes
medications.
Therefore, the increased risk of genital fungal infections can be considered a
class effect of
SGLT2 inhibitors. Glucosuria can potentially result in increased risk of
urinary tract
infection (UTI). In some clinical trials with SGLT2 inhibitors, the reported
rate of UTI was
slightly higher in subjects treated with a SGLT2 inhibitor compared to those
receiving
placebo.
SGLT2 inhibition leads to an increase in urinary excretion of glucose and
sodium, a diuretic
effect and a small decrease in blood pressure. In clinical trials with other
SGLT2 inhibitors,
this diuretic effect led to a slightly higher frequency of adverse events such
as pollakiuria,
thirst and polyuria, but these events were typically of mild severity and
usually did not lead
to discontinuation. However, certain populations of subjects may be at risk for
hypovolemiarelated
adverse events from this mechanism. As SGLT2 inhibition can lead to volume
depletion, there is a concern for potential adverse renal effects. In clinical
trials with other
SGLT2 inhibitors, early declines in the estimated glomerular filtration rate
(eGFR) were
seen, although there was a return toward baseline levels over time during
treatment and upon
discontinuation of therapy. This early eGFR decline is believed to be related
to dehydration
and not due to progressing renal insufficiency. However, the pattern of eGFR
decline
appeared to be different in subjects with varying degrees of baseline renal
function, with
greater persistence of eGFR decline in subjects with moderate renal impairment.
In addition,
in subjects with moderate renal impairment there was a slightly higher
incidence of renallyrelated
adverse events reported in subjects receiving SGLT2 inhibitors than in controls.
Routine safety monitoring for these adverse events will be performed in this
study.
The safety of ertugliflozin has been assessed in the clinical development
program in healthy
subjects as well as in subjects with T2DM. As of August 2013, a total of 479
subjects have
been exposed to ertugliflozin in six completed Phase 1 and two completed Phase
2 studies.
Oral doses of ertugliflozin as high as 300 mg (single dose), 100 mg once daily
(up to
14 days), and 25 mg once daily (up to 12 weeks) were well tolerated with a
safety profile
supporting continued development.
As of August 2013, there have been no deaths, and a total of 11 Serious Adverse
Events
(SAEs) were reported in 9 subjects. Across the program, a total of 10 subjects
(1.5%) were
withdrawn due to adverse events (AEs). The most frequent AEs reported with
ertugliflozin
use in the Phase 1 studies have been headache, constipation, diarrhea and
nausea. In the two
Phase 2 studies, upper respiratory, urinary tract and genital fungal
infections, diarrhea,
arthralgia and headache were most frequently reported. The incidence of these
AEs however
was low. Urinary tract infection was reported at a frequency of 3.3% for all
ertugliflozin
doses combined, versus 5.4% for placebo. The frequency of genital fungal
infection was
noted to be numerically higher in males and females receiving ertugliflozin
treatment
compared to placebo, and currently this AE is the only event considered to be
an adverse
drug reaction (ADR) for ertugliflozin. Overall, there was no clear dose-related
increase in
frequency of AEs with increasing dose of ertugliflozin.
In Phase 2 study B1521004, a mild diuretic effect was observed with
ertugliflozin
(ie, increase in 24-hour urinary volume) though there was a lack of a
dose-response
relationship across the doses of ertugliflozin evaluated, with the 25 mg dose
having a
numerically lower change from baseline in urine volume compared to the 5 mg
dose. This
diuretic effect from ertugliflozin could lead to volume depletion and related
adverse events
such as hypotension or dizziness, and these events will be monitored in the
Phase 3 studies.
In Phase 2, there were small increases observed in hemoglobin, hematocrit, and
blood-ureanitrogen
(BUN) suggestive of hemoconcentration, but no change in serum creatinine, at
Week 12 relative to Baseline. Given the small magnitude of the increases in
BUN, and
hemoglobin/hematocrit, these changes are unlikely to have clinical consequence.
Small
increases in serum phosphate and magnesium, though within the laboratory
reference range,
and an increase in intact parathyroid hormone (iPTH) were observed following 12
weeks of
dosing with ertugliflozin. There was a suggestion of changes in markers of bone
resorption,
though there did not appear to be a clear dose-dependent effect with increasing
dose of
ertugliflozin. In totality, the clinical relevance of these findings remains
unclear. However,
the effect of ertugliflozin on bone mineral density will be evaluated in a
Phase 3 trial, and all
clinical fractures will be adjudicated throughout the Phase 3 program by an
independent
committee.
In the clinical program to date, no clinically significant changes from
baseline in serum
aminotransferases (ALT and AST) and alkaline phosphatase have been observed.
Phase 3 clinical trial data from another SGLT2 inhibitor, dapagliflozin,
revealed a numerical
imbalance in the rates of breast and bladder cancer in dapagliflozin-treated
subjects
compared to control.11 The causal relationship to dapagliflozin for this
finding is uncertain
given the small number of events, confounding clinical factors and lack of
genotoxicity or
rodent carcinogenicity findings with dapagliflozin. No cancer imbalance,
including breast or
bladder cancer, was seen with another SGLT2 inhibitor, canagliflozin.
In summary, ertugliflozin belongs to a new class of medicines with a novel
mechanism of
action (MOA) that is independent of beta cell function and insulin secretion.
This suggests
that ertugliflozin could be suitable for subjects with various durations of
T2DM including
those with a long duration of T2DM with very little insulin secretion. The
glycosuria, with
associated diuresis, generated by ertugliflozin may provide additional benefits
such as weight
loss and blood pressure reduction. It is unclear if the changes in body weight
and blood
pressure will result in any clinically meaningful effects. Ertugliflozin can
cause genital
mycotic infections and a slight increase in urinary tract infections has been
seen in some
trials with SGLT2 inhibitors. Ertugliflozin through the osmotic diuretic effect
may be
associated with hypovolemia-related AEs.
Complete information for this compound may be found in the Single Reference
Safety
Document (SRSD), which for this study is the Investigators* Brochure for
ertugliflozin
(PF-04971729).
The U.S. FDA has warned that cases of a rare but serious infection of the
genitals and area around the genitals (called necrotizing fasciitis of the
perineum) have been reported with drugs that lower blood sugar in the same way
as ertugliflozin. Necrotizing fasciitis of the perineum may lead to
hospitalization and may require multiple surgeries. Seek medical attention
immediately if you have fever or you are feeling very weak, tired or
uncomfortable, and you develop tenderness, swelling, or redness of skin in the
area between and around your anus and genitals.
Linkstrasse 10
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Linkstrasse 10
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DE
Listed location countries
Age
Inclusion criteria
1. Subjects >= 40 years of age at the time of the initial Screening visit (V1) with a diagnosis of T2DM in accordance with American Diabetes Association (ADA) guidelines.13;2. HbA1c at the Screening visit (V1) of 7.0 10.5% (53 91 mmol/mol) on stable allowable AHA(s) or on no background AHA for at least 8 weeks prior to the Screening visit (V1).;3. Body Mass Index (BMI) >=18.0 kg/m2.;4. Subjects must have evidence or a history of atherosclerosis involving the coronary, cerebral or peripheral vascular systems as follows (must have at least one of the following a-d):;a. Coronary artery disease as indicated by a history of presumed spontaneous myocardial infarction (hospitalized with final diagnosis of myocardial infarction, excluding peri-procedural or definite secondary myocardial infarction [eg, due to profound anemia or hypertensive emergency, troponin increase in sepsis] in which the most recent event occurred at least 3 months (90 days) prior to the Screening visit (V1); OR;b. Coronary artery disease as indicated by a history of coronary revascularization through either a Percutaneous Coronary Intervention (PCI) at least 3 months (90 days) prior to the Screening visit (V1) or Coronary Artery Bypass Graft (CABG) at least 3 months (90 days) prior to the Screening visit (V1); OR;c. Ischemic (presumed thrombotic) cerebrovascular disease as indicated by a history of ischemic stroke (hospitalized with a final diagnosis of non hemorrhagic stroke [includes completion of a standard evaluation for stroke in an acute care facility or stroke clinic without hospital admission] with the most recent event occurring at least 3 months (90 days) prior to the Screening visit (V1) or a history of carotid revascularization at least 3 months (90 days) prior to the Screening visit (V1); OR;d. Peripheral arterial disease as indicated by:;1. Angiographically documented peripheral vascular disease; or;2. Resting ankle/brachial index (ABI) of <0.85 (measured by a certified vascular laboratory) plus symptoms of claudication; or;3. Amputation, peripheral bypass, or peripheral angioplasty of the extremities secondary to ischemia occurring at least 3 months (90 days) prior to the Screening visit (V1).;5. Subject meets one of the following criteria (a, b or c):;a. Is a male;;b. Is a female not of reproductive potential defined as one who (See Section 4.4.4.1 and Section 4.4.4.2 for reference on childbearing potential):;1. Is postmenopausal: defined as at least 12 months with no menses in women >=45 years of age. or;2. Has had a hysterectomy and/or bilateral oophorectomy, or had bilateral tubal ligation or occlusion at least 6 weeks prior to the Screening visit (V1).;c. Is a female of reproductive potential and:;1. Agrees to remain abstinent from heterosexual activity (if this form of birth control is accepted by local regulatory agencies and ethics review committees as the sole method of birth control); or;2. Agrees to use (or have their partner use) acceptable contraception to prevent pregnancy while the subject is receiving investigational product and for 14 days after the last dose of investigational product. Two methods of contraception will be used to avoid pregnancy. Acceptable combinations of methods include:;• Use of one of the following double-barrier methods: diaphragm with spermicide and a condom; cervical cap and a condom; or a contraceptive sponge and condom;;• Use of hormonal contraception (any registered and marketed contraceptive agent that contains an estrogen and/or a progestational agent [including oral, subcutaneous, intrauterine and intramuscular agents, and cutaneous patch]) with one of the following: diaphragm with spermicide; cervical cap; contraceptive sponge; condom; vasectomy; or intrauterine device (IUD);;• Use of an IUD with one of the following: condom; diaphragm with spermicide; contraceptive sponge; vasectomy; or hormonal contraception (see above);;• Vasectomy with one of the following: diaphragm with spermicide; cervical cap; contraceptive sponge; condom; IUD; or hormonal contraception (see above).;6. Evidence of a personally signed and dated informed consent document (ICD) indicating that the subject (or a legal representative) has been informed of all pertinent aspects of the trial. The subject may also provide consent for Future Biomedical Research. However, the subject may participate in the main trial without participating in Future Biomedical Research.;7. In the investigator*s opinion subjects are willing and likely able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures whether or not they receive investigational product for the duration of the trial.
Exclusion criteria
1. Subjects who had been previously randomized into this trial.;2. Subjects experiencing a cardiovascular event (eg, myocardial infarction or stroke) or undergoing coronary angioplasty or peripheral intervention procedure between the Screening visit (V1) and randomization.;3. Subjects undergoing any cardiovascular surgery (eg, valvular surgery) within 3 months (90 days) of the Screening visit (V1). ;4. Subjects with any planned coronary revascularization or peripheral intervention procedure or other cardiovascular surgery.;5. Subjects with New York Heart Association (NYHA) Class III or IV heart failure at the Screening visit (V1).;6. Mean value for triplicate screening sitting systolic blood pressure >160 mm Hg and/or diastolic blood pressure >90 mm Hg after at least a 5 minute seated rest at the Screening visit (V1), confirmed via 1 repeat triplicate set at the Screening visit (V1) if deemed necessary. For subjects with a mean triplicate value of sitting systolic blood pressure >160 mm Hg and/or diastolic blood pressure >90 mm Hg after at least a 5 minute seated rest at the Screening visit (V1) the investigator or the treating physician is allowed to adjust background blood pressure medication(s) to lower blood pressure values in order for the subject to be re-assessed for enrollment eligibility. ;7. Subject has a clinically significant ECG abnormality at Screening visit (V1) that requires further diagnostic evaluation or intervention (eg, new, clinically significant arrhythmia or a conduction disturbance). ;8. History of type 1 diabetes mellitus or a history of ketoacidosis. ;9. History of other specific types of diabetes (eg, genetic syndromes, secondary pancreatic diabetes, diabetes due to endocrinopathies, drug- or chemical induced, and post organ transplant).;10. Subject has active, obstructive uropathy or indwelling urinary catheter. ;11. Subject has a history of malignancy <=5 years prior to signing informed consent, except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer. ;Note (1) A subject with a history of malignancy >5 years prior to signing informed consent should have no evidence of residual or recurrent disease. ;Note (2) A subject with any history of melanoma, leukemia, lymphoma, or renal cell carcinoma is excluded.;12. Subject routinely consumes >2 alcoholic drinks per day or >14 alcoholic drinks per week, or engages in binge drinking. ;Note (1): One alcoholic drink is defined as 5 oz (150 mL) of wine, or 12 oz (350 mL) of beer, or 1.5 oz (50 mL) of 80 proof liquor.;Note (2): Binge drinking is defined as a pattern of 5 or more alcoholic drinks (male), or 4 or more alcoholic drinks (female) in about 2 hours.;13. Any clinically significant malabsorption condition.;14. Subjects with a known hypersensitivity or intolerance to any SGLT2 inhibitor.;15. Screening fasting plasma or finger stick glucose >270 mg/dL (15 mmol/L), confirmed by a single repeat following counseling on exercise and diet. ;16. History of one or more severe hypoglycemic episodes within 6 months of Screening (V1) or a severe hypoglycemic episode occurring during the interval between the Screening visit (V1) and randomization.;17. Fasting triglycerides >600 mg/dL (6.78 mmol/L) at Screening (V1), confirmed by a single repeat if deemed necessary. For subjects with fasting triglycerides >600 mg/dL the investigator or treating physician is allowed to adjust background lipid altering medication(s) to lower fasting triglycerides in order for the subject to be re-assessed for enrollment eligibility. ;18. Subjects currently taking blood pressure or lipid altering medications that have not been on a stable dose for at least 4 weeks prior to randomization. Subjects who require a change in blood pressure and/or lipid altering medications to meet the entry criteria related to blood pressure and/or triglycerides must be on a stable dose of such therapy for at least 4 weeks prior to randomization. ;19. Subjects who meet any of the following categories:;• Subject is on a weight-loss program and is not weight-stable.;• Subject is on a weight-loss medication (eg, orlistat, phentermine/topiramate, lorcaserin) and is not weight-stable.;• Subject is on other medications associated with weight changes (eg, anti-psychotic agents) and is not weight-stable.;• Subject has undergone bariatric surgery >12 months prior to Visit 1/Screening and is not weight-stable.;• Subject has undergone bariatric surgery within 12 months of Screening visit (visit 1).;Note: Weight-stable is defined as <5% change in body weight in the last 6 months.;20. Subjects currently being treated for hyperthyroidism, subjects on thyroid replacement therapy that have not been on a stable dose for at least 6 weeks prior to the Screening visit (V1) and/or subjects who have a TSH outside of the laboratory reference range at the Screening visit (V1).
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
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In other registers
Register | ID |
---|---|
Other | 01986881 |
EudraCT | EUCTR2013-002518-11-NL |
CCMO | NL46397.068.13 |