Primary objectiveIn subjects with T2DM receiving standard of care but with inadequate glycemic control and at elevatedrisk of cardiovascular (CV) events to assess the effect of canagliflozin compared to placebo onprogression of albuminuria.Secondary…
ID
Source
Brief title
Condition
- Cardiac disorders, signs and symptoms NEC
- Diabetic complications
- Nephropathies
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Progression is the development of microalbuminuria or macroalbuminuria in a
subject with baseline
normoalbuminuria or the development of macroalbuminuria in a subject with
baseline microalbuminuria,
accompanied by an ACR value increase of greater than or equal to 30% from
baseline.
The primary outcome is progression of albuminuria (as defined above). If the
ACR at a visit meets the
definition of progression described above, a repeat ACR collection
approximately 1 to 2 months later (or
sooner under unusual circumstances, eg, subject is stopping study drug) must
confirm progression of
albuminuria (ie, confirmed progression). If the last on-treatment value meets
the definition of progression
and no repeat ACR collection can be made, the subject will also be deemed to
have progressed.
ACR assessments will be based upon values obtained from first morning void
urines analyzed by the
central laboratory. In this study, duplicate urine specimens will be collected
for all ACR measurements.
Secondary outcome
The secondary outcomes are:
* Regression of albuminuria is the development of normoalbuminuria in a subject
with baseline
microalbuminuria or macroalbuminuria or the development of microalbuminuria in
a subject with
baseline macroalbuminuria, accompanied by a decrease in the urinary ACR value
of greater than or
equal to 30% from baseline. If the ACR at a visit meets the definition of
regression described above,
a repeat on-treatment ACR collection approximately 1 to 2 months later (or
sooner under unusual
circumstances, eg, subject is stopping study drug), must confirm regression of
albuminuria
(ie, confirmed regression). If the last on-treatment value meets the definition
of regression and no
repeat ACR collection can be made, the subject will also be deemed to have
regressed.
* Change in eGFR from baseline to the last off-treatment value done
approximately 30 days post study
drug discontinuation.
* Urinary albumin/creatinine ratio at last on-treatment visit.
Safety outcomes
The data from this study will be combined with the data from another
large-scale study of the effects of
canagliflozin compared to placebo (CANVAS) in a pre-specified meta-analysis of
cardiovascular safety
outcomes to satisfy the US FDA Post Marketing Requirements.
Background summary
Canagliflozin (JNJ-28431754) is an inhibitor of the sodium-glucose
co-transporter 2 (SGLT2) that has
been developed as an oral antihyperglycemic agent (AHA) for the treatment of
patients with type 2
diabetes mellitus (T2DM).
In March 2013, canagliflozin was approved for marketing by the United States
(US) Food and Drug
Administration (FDA). An ongoing clinical program designed to continue research
on the effects of the
agent on renal and cardiovascular outcomes is underway. The goal of this study
is to assess the effects of
canagliflozin compared to placebo on the progression of albuminuria, an
important intermediate marker
of renal injury and progression of diabetic nephropathy.
Study objective
Primary objective
In subjects with T2DM receiving standard of care but with inadequate glycemic
control and at elevated
risk of cardiovascular (CV) events to assess the effect of canagliflozin
compared to placebo on
progression of albuminuria.
Secondary objectives
In subjects with T2DM receiving standard care but with inadequate glycemic
control and at elevated risk
of CV events to assess the effect of canagliflozin compared to placebo on:
* Regression of albuminuria
* Change in glomerular filtration rate (eGFR) from baseline to the last
off-treatment value done
approximately 30 days post study drug discontinuation
* Urinary albumin/creatinine ratio (ACR)
Exploratory objectives
In subjects with T2DM receiving standard care but with inadequate glycemic
control and at elevated risk
of CV events to assess the effect of canagliflozin compared to placebo on:
* Change in eGFR determined from a between group comparison of the eGFR slopes
using all
on-treatment measures of eGFR made from the first on-treatment measurement to
the final
on-treatment measurement
* Changes in HbA1c
* Utilization of AHA therapy
Safety objective
Cardiovascular safety data from this study will be combined with the data from
the other large-scale study
of the effects of canagliflozin compared to placebo (CANVAS; 28431754DIA3008; A
Randomized,
Multicenter, Double-Blind, Parallel, Placebo-Controlled Study of the Effects of
Canagliflozin on
Cardiovascular Outcomes in Adult Subjects With Type 2 Diabetes Mellitus;
NCT01032629) in a
pre-specified meta-analysis of cardiovascular safety outcomes.
Study design
This is a randomized, double-blind, placebo-controlled, parallel-group,
multicenter study to evaluate the
effects of canagliflozin compared to placebo on progression of albuminuria, an
important intermediate
marker of renal injury and progression of diabetic nephropathy. The study will
be conducted in subjects
with T2DM, receiving standard of care for hyperglycemia and CV risk factors,
who have either a history
or high risk of CV events. A total of 5,700 subjects will be recruited into the
study. The study*s last
subject last visit is targeted to occur when the last subject randomized has
approximately 78 weeks of
follow-up or when 688 major adverse cardiovascular events (MACE) events (ie, CV
death, nonfatal
myocardial infarction, nonfatal stroke) are accumulated between the CANVAS and
CANVAS-R
(DIA4003) studies, whichever comes later (estimated to occur between January
2017 and April 2017).
The effects of canagliflozin will be evaluated against a background of standard
of care for the treatment
of hyperglycemia and CV risk factors with study investigators counseled to
assure appropriate
management according to applicable national guidelines for the care of patients
with T2DM with
treatment individualized as clinically appropriate.
Intervention
Upon successful completion of screening, all potentially eligible individuals
will enter a 2-week run-in
period, during which they will receive single-blind placebo capsules (one
capsule to be taken once-daily)
to assess compliance.
Individuals that meet inclusion/exclusion criteria and that are compliant
during run-in will be randomly
assigned in a 1:1 ratio to canagliflozin or matching placebo to be taken once
daily, before the first meal of
the day. Canagliflozin will be provided at the dose of 100 mg/day through Week
13 and then increased at
the discretion of the investigator at Week 13 or a subsequent visit to the dose
of 300 mg/day, if the subject
requires additional glycemic control and is tolerating the 100 mg dose (see
Protocol Section 3.1). All study drug
after randomization will be provided in a double-blind manner.
During the study, the subjects will visit maximum 11 times research centre. In
addition there are six telephone contacts. During the visits, blood and urine
will be collected for analysis and the vital signs of the patient are measured.
Study burden and risks
Burden:
1. Up to 11 visits spread over 3.5 years;
2. Up to 6 telephone contacts / email contacts about 3.5 years;
3. 11 blood samples (including 6 times sober) and 10 times urine collection
over 3.5 years
Risks:
1. Side effects of canagliflozine;
2. Risks from side effects of testing (eg bloodsampling)
3. Unknown risks
Dr. Paul Janssenweg 150
Tilburg 5026 RH
NL
Dr. Paul Janssenweg 150
Tilburg 5026 RH
NL
Listed location countries
Age
Inclusion criteria
- Man or woman with a diagnosis of T2DM with HbA1c level * 7.0% to * 10.5% at screening
and be either (1) not currently on AHA therapy or (2) on AHA monotherapy or combination
therapy with any approved agent: eg, sulfonylurea, metformin, pioglitazone,
alpha-glucosidase inhibitor, GLP-1 analogue, DPP-4 inhibitor, or insulin.;- History or high risk of CV events defined on the basis of either:
Age *30 years with documented symptomatic atherosclerotic CV events:
including stroke; MI; hospital admission for unstable angina; coronary artery bypass
graft; percutaneous coronary intervention (with or without stenting); peripheral
revascularization (angioplasty or surgery); symptomatic with documented
hemodynamically-significant carotid or peripheral vascular disease; or amputation
secondary to vascular disease.
2) age * 50 years with 2 or more of the following risk factors determined at the screening
visit: duration of T2DM of 10 years or more, systolic blood pressure >140 mmHg
(average of 3 readings) recorded at the Screening Visit, while the subject is on at least
one blood pressure-lowering treatment, current daily cigarette smoker, documented
micro- or macroalbuminuria (see Section 3.2, Study Design Rationale, for definition)
within one year of screening, or documented HDL-C of <1 mmol/L (<39 mg/dL) within
one year of screening.
Note: An overall target ratio of approximately 70%:30% for CV history (first
category):risk factors (second category) will be implemented (with a maximum of
approximately 40% in the second category). This target is intended to be a global ratio
and may vary by region. The proportion of subjects in these categories will be
monitored centrally.
Note: the term *documented* in the above paragraphs refers to the required information
being clearly noted in hospital/clinical records or in physician-referral documents,
copies of which should be retained in the subject*s study files.;- Women must be:
postmenopausal, defined as
o >45 years of age with amenorrhea for at least 18 months, or
o >45 years of age with amenorrhea for at least 6 months and less than 18 months
and a known serum follicle stimulating hormone (FSH) level >40 IU/L, or
o surgically sterile (have had a hysterectomy or bilateral oophorectomy, tubal occlusion),
or otherwise be incapable of pregnancy, or
o heterosexually active and practicing a highly effective method of birth control,
including hormonal prescription oral contraceptives, contraceptive injections,
contraceptive patch, intrauterine device, double-barrier method (eg, condoms,
diaphragm, or cervical cap with spermicidal foam, cream, or gel), or male partner
sterilization, consistent with local regulations regarding use of birth control methods for
subjects participating in clinical trials, for the duration of their participation in the study,
or
o not heterosexually active.
Note: subjects who are not heterosexually active at screening must agree to utilize a
highly effective method of birth control if they become heterosexually active during
their participation in the study.;- Women of childbearing potential (ie, those subjects who do not meet the postmenopausal
definition above, regardless of age) must have a negative urine pregnancy test at baseline
(Day 1) and at screening if required by local regulations (Note: a serum pregnancy test is
acceptable in lieu of a urine pregnancy test if required by local regulations).;- Willing and able to adhere to the prohibitions and restrictions specified in this protocol
- Subjects must have signed an informed consent document indicating that they understand
the purpose of and procedures required for the study and are willing to participate in the
study;Inclusion Criterion for Randomization
- Subjects must have taken *80% of their single-blind placebo doses during the 2-weeks prior
to randomization on Day 1 to be eligible for randomization.
Exclusion criteria
Potential subjects who meet any of the following criteria will be excluded from participating in
the study:;Diabetes-Related/Metabolic
- History of diabetic ketoacidosis, T1DM, pancreas or beta-cell transplantation, or diabetes
secondary to pancreatitis or pancreatectomy
- History of one or more severe hypoglycemic episodes within 6 months before screening
Note: a severe hypoglycemic episode is defined as an event that requires the help of another
person.
- History of hereditary glucose-galactose malabsorption or primary renal glucosuria
- Ongoing, inadequately controlled thyroid disorder
Note: subjects on thyroid hormone replacement therapy must be on a stable dose for at least
6 weeks before Day 1.;Renal/Cardiovascular
- Renal disease that required treatment with immunosuppressive therapy or a history of
chronic dialysis or renal transplant. Note: subjects with a history of treated childhood renal
disease, without sequelae, may participate.
- Myocardial infarction, unstable angina, revascularization procedure, or cerebrovascular
accident within 3 months before screening, or a planned revascularization procedure, or
history of New York Heart Association (NYHA) Class IV cardiac disease (The Criteria
Committee of the New York Heart Association).
- Known ECG findings within 3 months before screening that would require urgent diagnostic
evaluation or intervention (eg, new clinically important arrhythmia or conduction
disturbance);Gastrointestinal
- Known history of hepatitis B surface antigen or hepatitis C antibody positive (unless known
to be associated with documented persistently stable/normal range aspartate
aminotransferase [AST] and alanine aminotransferase [ALT] levels), or other clinically
active liver disease
- Any history of or planned bariatric surgery;Laboratory
- eGFR <30 mL/min/1.73m2 at screening visit
- ALT levels >2.0 times the upper limit of normal (ULN) or total bilirubin >1.5 times the
ULN, unless in the opinion of the investigator and as agreed upon by the sponsor*s medical
officer, the findings are consistent with Gilbert*s disease;Other conditions
- History of malignancy within 5 years before screening (exceptions: squamous and basal cell
carcinomas of the skin and carcinoma of the cervix in situ, or a malignancy that in the
opinion of the investigator, with concurrence with the sponsor*s medical monitor, is
considered cured with minimal risk of recurrence)
- History of human immunodeficiency virus (HIV) antibody positive
- Subject has a current clinically important hematological disorder (eg, symptomatic anemia,
proliferative bone marrow disorder, thrombocytopenia)
- Investigator*s assessment that the subject*s life expectancy is less than 1 year, or any
condition that in the opinion of the investigator would make participation not in the best
interest of the subject, or could prevent, limit, or confound the protocol-specified safety or
efficacy assessments
- Major surgery (ie, requiring general anesthesia) within 3 months of the screening visit or any
surgery planned during the subject*s expected participation in the study (except minor
surgery, ie, outpatient surgery under local anesthesia)
- Any condition that, in the opinion of the investigator, would compromise the well-being of
the subject or prevent the subject from meeting or performing study requirements
Medications/Therapies
- Current or prior use of an SGLT2 inhibitor.
- Prior or current participation in another canagliflozin study.
- Known allergies, hypersensitivity, or intolerance to canagliflozin or its excipients (refer to
Section 14.1, Physical Description of Study Drug[s])
- Current use of a corticosteroid medication or immunosuppressive agent, or likely to require
treatment with a corticosteroid medication (for longer than 2 weeks in duration) or an
immunosuppressive agent. Note: subjects using inhaled, intranasal, intra-articular, or topical
corticosteroids, or corticosteroids in therapeutic replacement doses may participate
- Received an active investigational drug (including vaccines) or used an investigational
medical device within 3 months before Day 1/baseline;General
- History of drug or alcohol abuse within 3 years before screening
- Pregnant or breast-feeding or planning to become pregnant or breast-feed during the study
- Employees of the investigator or study center, with direct involvement in the proposed study
or other studies under the direction of that investigator or study center, as well as family
members of the employees or the investigator
Note: Investigators should assure that all study enrollment criteria have been met and
determine that the subject has not had any interval change in clinical status since screening.
Before randomization, subjects whose status changes after screening, such that they now
meet an exclusion criterion, should be excluded from participation.
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 | EUCTR2013-003050-25-NL |
| CCMO | NL47109.018.13 |