Primary Efficacy Objectives:The primary efficacy objective of this trial is to evaluate the placebo-adjusted change in HbA1c from baseline after 24 weeks of exposure to bexagliflozin in type 2 diabetic subjects with increased risk of cardiovascular…
ID
Source
Brief title
Condition
- Heart failures
- Glucose metabolism disorders (incl diabetes mellitus)
- Arteriosclerosis, stenosis, vascular insufficiency and necrosis
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary efficacy endpoint:
* Change in HbA1c from baseline to week 24, compared to placebo
Secondary outcome
Secondary efficacy endpoints:
* Change in body weight from baseline to week 48 in subjects with a BMI * 25
kg/m2
* Change in SBP from baseline to week 24 in subjects with baseline systolic
blood pressure * 140 mmHg
Exploratory efficacy end points:
* Change in HbA1c from baseline over time
* Change in FPG from baseline over time
* Change in body weight from baseline over time
* Change in SBP over time
* Requirement of additional anti-diabetic medications, including insulin, over
time
* Requirement of reduced anti-diabetic medications, including insulin, over time
* Incidence of hospitalization for heart failure among all subjects and among
subjects who have a history of heart failure
Other endpoint:
Samples for population PK analysis will be collected and the plasma
concentration of bexagliflozin determined. The PK parameters will be assessed
separately as part of the population PK analysis. Biomarker samples will be
collected. The biomarker analysis will be performed separately.
Safety Assessments:
The safety endpoints will include:
* A 5-point composite endpoint of CV death, non-fatal MI, non-fatal stroke,
hospitalization for unstable angina, or coronary revascularization
* A 6-point composite endpoint of CV death, non-fatal MI, non-fatal stroke,
hospitalization for unstable angina, coronary revascularization or
hospitalization for heart failure
* Individual events including all-cause mortality, CV death, fatal and
non-fatal MI, fatal and non-fatal stroke, hospitalization for unstable angina,
hospitalization for CHF, or coronary revascularization. Both first events and
total events, taking account of repeat events will be examined
* Change in eGFR from baseline
* Change in UACR from baseline
* Incidence of adverse events of interest. Adverse events of interest including
urinary tract infections including urosepsis and pyelonephritis, genital
mycotic infections, diuretic effects including hypovolemia, hypotension
episodes, hypoglycemia, hepatotoxicity, falls and fractures, malignancies,
hypersensitivity reactions, acid-base disorders, and renal failure events
Other safety assessments:
**Adverse events
**Clinical laboratory events
**Physical examinations
**Vital signs including orthostatic blood pressure
**Use of concomitant medications
Background summary
(See protocol point 1)
Type 2 diabetes mellitus (T2DM) is one of the leading causes of morbidity and
mortality worldwide, affecting an estimated 382 million people in 2013 (IDF,
2014). More than 95% of people with diabetes have type 2 diabetes, and more
than 80% of those with T2DM are overweight or obese. In Western societies,
individuals with diabetes have at least twice the risk of hypertension and
major cardiovascular complications compared to individuals without diabetes
(Bhatt et al., 2010; Preis et al., 2009; Sarwar et al., 2010) and the major
cause of death among patients with T2DM is cardiovascular disease (Go et al.,
2013). In addition, congestive heart failure is highly prevalent among men and
women with T2DM, and T2DM increases the occurrence of heart failure
independently of underlying coronary disease (Boudina and Abel, 2007; Domanski
et al., 2003; Kannel and McGee, 1979).
Although glycemic control clearly reduces microvascular diabetic complications
(ADA, 2013), it is less clear whether any specific approach to reducing blood
glucose concentration, particularly among patients with long standing T2DM or
established cardiovascular risk factors, confers additional risk with respect
to cardiovascular events (Duckworth et al., 2009; Patel et al., 2008). As a
result of this uncertainty, both FDA and European Medicines Agency (EMA)
require demonstration of long-term cardiovascular safety prior to the approval
of new drugs for treatment of T2DM (FDA Guidance 2008, ucm071627.pdf).
The renal Na+/glucose transport protein (SGLT2) actively transports
extracellular glucose into cells using the driving energy of the transmembrane
electrochemical potential for sodium ions. Individuals with disruptions in
SLC5A2, the gene encoding SGLT2, exhibit prominent glucosuria in the absence of
significant co-morbidities (Santer et al., 2003; van den Heuvel et al., 2002).
The excretion of glucose in the urine of diabetic subjects in
amounts comparable to or greater than that seen in individuals harboring loss
of functions mutations in SLC5A2 has the potential to improve both fasting and
postprandial hyperglycemia without increasing insulin secretion, causing weight
gain, or inducing hypoglycemia. Several SGLT2 inhibitors have demonstrated
these clinical benefits as a mono- or combination therapy with other oral
anti-diabetic medications including insulin
(Nauck, 2014). Studies of the three SGLT2 inhibitors licensed in the US,
dapagliflozin, canagliflozin, and empagliflozin, have demonstrated that long
term use of an SGLT2 inhibitor does not increase the incidence of major adverse
cardiovascular events (MACE). Because heart failure is exacerbated by fluid
retention, the development of diuretic oral antidiabetic agents is potentially
attractive for the treatment of diabetic patients with comorbid heart failure
and may be similarly attractive in patients with both diabetes and
hypertension.
Study objective
Primary Efficacy Objectives:
The primary efficacy objective of this trial is to evaluate the
placebo-adjusted change in HbA1c from baseline after 24 weeks of exposure to
bexagliflozin in type 2 diabetic subjects with increased risk of cardiovascular
adverse events.
Secondary Efficacy Objectives:
The key secondary efficacy objectives are:
* To evaluate the effect of bexagliflozin on the change in body weight from
baseline to week 48 in randomized subjects with a BMI * 25 kg/m2 compared to
placebo
* To evaluate the effect of bexagliflozin on the change in systolic blood
pressure (SBP) from baseline to week 24 in subjects with Baseline systolic
blood pressure * 140 mmHg compared to placebo
Additional exploratory efficacy objectives are:
* To assess the effect of bexagliflozin treatment on the change in HbA1c versus
placebo over time
* To evaluate the effect of bexagliflozin treatment on the change in fasting
plasma glucose (FPG) versus placebo over time
* To measure the proportion of subjects requiring an intensification of
antidiabetic regimen versus placebo over time
* To measure the proportion of subjects requiring a relaxation of their
antidiabetic regimen versus placebo over time
* To measure the incidence of hospitalization for heart failure among all
subjects and among subjects with a history of heart failure at baseline
Safety Objectives:
The primary safety objective of this study is the contribution of at least 134
major adverse cardiovascular events (MACE+) to an eventual meta-analysis that
is intended to exclude a hazard ratio of 1.8 or greater for subjects exposed to
bexagliflozin compared to subjects exposed to placebo. MACE+ is defined as
cardiovascular death, non-fatal myocardial infarction (MI), non-fatal stroke,
or hospitalization for unstable angina.
An additional objective is the evaluation of the safety of exposure to
bexagliflozin for a minimum of 52 weeks in a treatment population that is at
elevated risk for major adverse cardiovascular events.
Other Objectives:
Measurement of bexagliflozin plasma concentration as a function of time from
dosing (sparsely sampled) will be conducted at 30 sites and will include
approximately 240 subjects.
Measurement of cardiovascular biomarkers at baseline and week 12 in an
exploratory study to increase the understanding of bexagliflozin treatment
effect on the biomarkers that are relevant in the CV disease diagnosis and
prognosis
Study design
THR-1442-C-476 is a multi-center, randomized, double-blind, placebo-controlled,
parallelgroup study. Approximately 1650 subjects with sub-optimally controlled
T2DM and elevated risk for cardiovascular adverse events will be randomized to
bexagliflozin tablets, 20 mg, or placebo in a 2:1 ratio as an add-on therapy to
background anti-diabetic medications
Intervention
* Protocol scheduled subject visits
* Diet & exercise counseling (at visit 2)
* Diary & glucometer records (reviewed at each visit)
* PK sampling (visits 5 & 6)
Study burden and risks
Possible risks of bexagliflozin:
Bexagliflozin has been tested in animals and humans (A total of 10 studies have
been conducted in healthy volunteers and subjects with type 2 diabetes).
Overall, bexagliflozin has been well tolerated by subjects. A very common side
effect that is associated with bexagliflozin use is headache (one in ten
patients). Common side effects include sore throat, muscle pain, and frequent
urination (occurred between one in ten and one in a hundred patients). There
have been a few patients that discontinued participation of a clinical trial
due to adverse events that the study doctor considered to be related to
bexagliflozin treatment. These adverse events were skin rash, temporary blurry
vision, and creatinine increase (indicating a decrease in kidney function). You
must tell the study doctor or study staff about all side effects that you
have. If you are not honest about your side effects, it may not be safe for
you to stay in the study.
Before experimental drugs are given to human subjects they are given to animals
at doses much higher than used in humans to see what kind of bad effects they
may produce. Not all of the bad effects seen in animals may be seen in humans,
and some bad effects may occur in humans that were never seen in animals.
Animals given doses much higher than what will be given during this study have
experienced effects on the digestive system, such as diarrhea and stomach
irritation, and effects on the liver, kidney, and heart. No such reactions have
been observed in humans receiving up to 100 mg doses of bexagliflozin.
Studies have been conducted in humans with other drugs similar to
bexagliflozin. These drugs have been generally well tolerated. The possible
side effects of SGLT2 inhibitors include dehydration, kidney problems, low
blood sugar when this class of medicines is combined with other prescription
medicines used to treat diabetes, increased cholesterol in the blood, and yeast
infection. A rare side effect called ketoacidosis has been experienced in some
diabetic patients who have taken SGLT2 inhibitors. Ketoacidosis is a condition
when the body produces high levels of blood acids. If you experience difficulty
breathing, nausea, vomiting, abdominal pain, confusion, and unusual fatigue or
sleepiness, you must contact your study doctor. The number of events is only
slightly higher than the number of side effects in people taking a placebo.
Side effects that were not included as risks in the previous consent form are
bronchitis, influenza, back pain, upper respiratory tract infection, muscle
spams, dizziness and hypertension.
Unforeseen risks: Since the study medication is experimental, there may be
other side effects (risks) that are not known. All drugs have a potential risk
of an allergic reaction, which if not treated promptly, could become
life-threatening.
Side effects of other study-related medication
It is important to know that there may be other side effects that are not yet
known. Side effects may go away after the treatment is stopped, but it is also
possible that side effects may last a long time or may never go away. They may
range from mild to life threatening and/or fatal.
It is important to tell the study doctor or study nurse right away about any
changes in health that may have happened even if you do not think they are
related to the study or to the medication. Your study doctor may give you
treatment to help control side effects.
Pregnancy risks for Female Participants
The effects of the study drug on an unborn child and on a breast-fed baby are
not known. Because of this, it is very important that you are not pregnant and
are not breast-feeding and you do not become pregnant during the course of the
study. You will not be allowed to take part in the study if you are pregnant,
trying to become pregnant or are breast-feeding.
* If you can become pregnant, the study doctor will ask you to have a urine
pregnancy test before you start the study, and during the study to make sure
that you are not pregnant.
* If you can become pregnant, you must practice abstinence or use a reliable
birth control method(s) for the duration of the study. Your study doctor will
let you know which birth control methods are acceptable. The following birth
control methods are recommended: oral contraceptives, intrauterine device,
Depo-Provera, Norplant, hormonal contraceptive implants, bilateral tubal
ligation, partner with vasectomy, condom or diaphragm plus contraceptive
sponge, foam, or jelly.
* If you become pregnant while taking part in the study you should let your
study doctor know right away. Your study doctor will remove you from the study
and talk to you about the need for further medical attention if appropriate.
If you become pregnant, we ask that you allow us to collect information on your
pregnancy and your child for at least 6 months after your child*s birth.
What are the possible benefits and disadvantages of taking part in this
research study?
Possible benefits from taking part in this study may include:
* Your health problem may get better from taking part in this study. In this
study you may get placebo which means you may not be taking bexagliflozin
during the study.
* Taking part in this study will help doctors to learn more about
bexagliflozin. This may help others with your health problem in the future.
255 Cedar Hill St. Suite 200
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US
Listed location countries
Age
Inclusion criteria
The study population will include:
1. Male or female adult subjects with an age *40 years
2. Subjects with a diagnosis of T2DM
3. Subjects with HbA1c values of 7.5 * 11%, inclusive
4. Subjects with fasting plasma glucose (FPG) * 250 mg/dL at screening
5. Subjects who have a regimen for treatment of T2DM that has been stable for
the past 3 months. A stable regimen is defined as: no changes in dose or
frequency of OHAs or GLP-1 agonists, or <20% variability in total daily insulin
dose
6. Subjects who present with at least one of the following 3 histories:
Group 1: A history of atherosclerotic vascular disease as defined by one or
more of the following:
a) myocardial infarction (MI) or ischemic (non-hemorrhagic) stroke > 3 months
but * 5 years prior to screening or
b) documented history of coronary, carotid, or peripheral arterial
revascularization (coronary artery bypass grafting must have occurred * 5 years
prior to screening)
Group 2: A history of NYHA class II or class III heart failure at the time of
screening with a left ventricular ejection fraction (LVEF) * 40% and no
subsequent LVEF > 40% documented within 6 months of screening. No more than 200
subjects with class II NYHA heart failure will be randomized in the study
Group 3: Age * 55 years with 2 or more of the following:
a) diabetes duration of * 10 years
b) uncontrolled hypertension defined as SBP > 140 mmHg despite 3 or more
anti-hypertensive medications
c) current smoking
d) urine albumin:creatinine ratio (UACR) > 30 mg/g
e) eGFR of 45 to 60 mL/min/1.73 m2, or
f) HDL < 1 mmol/L (38 mg/dL)
7. Female subjects of childbearing potential who are willing to use an adequate
method of contraception and to not become pregnant for the duration of the
study. Adequate contraceptive measures include, but are not limited to, oral
contraceptives, intrauterine devices, Depo-Provera, Norplant, hormonal
contraceptive implants, bilateral tubal ligation, partner with vasectomy,
condom or diaphragm plus contraceptive sponge, foam, or jelly, and abstinence
8. Subjects who are willing and able to return for all clinic visits and to
complete all study required procedures, including self-monitored blood glucose
(SMBG) measurement, and take run-in medication, missing no more than one dose
9. Subjects who receive anti-hypertensive medications at a stable dosage for *
2 weeks prior to randomization
10. Subjects who receive lipid modifying therapy on a stable regimen for 6
weeks prior to randomization
11. Subjects who have seated SBP < 170 mmHg and DBP < 110 mmHg at screening
Exclusion criteria
Patients who exhibit any of the following characteristics will be excluded from
the study:
1. Diagnosis of type 1 diabetes mellitus or maturity*onset/diabetes of the
young (MODY)
2. Hemoglobinopathy that affects HbA1c measurement
3. Frequent symptomatic hypoglycemia (greater than one episode per week on
average)
4. Genitourinary tract infection within 6 weeks of screening or history of * 3
genitourinary infections requiring treatment within the last 6 months
5. Cancer, active or in remission for < 3 years (Non-melanoma skin cancer or
basal cell carcinoma or carcinoma in situ of the cervix will not be grounds for
exclusion)
6. History of alcohol or illicit drug abuse in the past 2 years
7. Evidence of abnormal liver function tests (total bilirubin or alkaline
phosphatase > 1.5 x upper limit of normal (ULN) with the exception of isolated
Gilbert*s syndrome); or alanine aminotransferase (ALT) or aspartate
aminotransferase (AST) > 2.5 x ULN
8. History of MI, stroke or hospitalization for heart failure in the prior 3
months
9. Evidence of NYHA class IV heart failure at screening or randomization
10. Presently scheduled for percutaneous coronary intervention, coronary artery
bypass grafting or any surgical procedure
11. Previous treatment with bexagliflozin or EGT0001474
12. Currently or within 3 months of taking any SGLT2 inhibitors
13. Any condition, disease, disorder, or clinically relevant laboratory
abnormality that, in the opinion of the PI, would jeopardize the subject*s
appropriate participation in this study or obscure the effects of treatment
14. Prior renal transplantation or evidence of nephrotic syndrome, defined as a
urine albumin: creatinine ratio (UACR) > 2000 mg/g, at screening
15. Implantation of a cardiac resynchronization therapy device within 3 months
prior to screening or intent to implant a cardiac resynchronization therapy
(CRT) within 6 months following screening
16. Diagnosis of peripartum or chemotherapy-induced cardiomyopathy within 12
months prior to screening
17. Symptomatic bradycardia or second or third degree atrioventricular block
without a pacemaker
18. eGFR, as calculated by the modification of diet in renal disease study
equation (MDRD), < 45 mL/min/1.73 m2 or requiring dialysis
19. Pregnant or nursing
20. Currently participating in another interventional trial
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 |
|---|---|
| EudraCT | EUCTR2015-001760-19-NL |
| ClinicalTrials.gov | NCT02558296 |
| CCMO | NL55821.028.15 |