| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| type 2 diabetes mellitus (T2DM) with inadequate glycemic control on combination therapy with metformin and a sulphonylurea (SU) |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 12.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10067585 |
| E.1.2 | Term | Type 2 diabetes mellitus |
|
| 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 the effect of canagliflozin relative to placebo on HbA1c after 26 weeks of treatment.
• To assess the safety and tolerability of canagliflozin
|
|
| E.2.2 | Secondary objectives of the trial |
After 26 weeks of treatment, to assess the effect of canagliflozin relative to placebo on:
•Fasting plasma glucose (FPG)
•Proportion of subjects with HbA1c <7.0% and <6.5%
•Body weight
•Fasting plasma lipids (ie, low-density lipoprotein cholesterol [LDL-C], high density lipoprotein cholesterol [HDL-C], total cholesterol, LDL-C to HDL-C ratio, and triglycerides)
•Systolic and diastolic blood pressure
•Time to rescue therapy and proportion of subjects receiving rescue therapy
•Fasting measure of beta-cell function (ie, HOMA-B)
After 52 weeks of treatment, to assess the effect of canagliflozin relative to placebo on:
•Glycemic control (HbA1c and FPG)
•Body weight
•Proportion of subjects with HbA1c <7.0% and <6.5%
•Fasting plasma lipids (ie, LDL-C, HDL-C, total cholesterol, LDL-C to HDL-C ratio, and triglycerides)
•Systolic and diastolic blood pressure
•Time to rescue therapy and proportion of subjects receiving rescue therapy...
|
|
| 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 |
To augment information obtained from HbA1c and FPG, this study includes a frequently sampled standard meal tolerance test (FS MMTT) in approximately 25% of subjects with collection of post-meal glucose levels. This procedure will provide information on the effect of canagliflozin on post meal glucose as well as on measures of insulin secretion and insulin sensitivity. Additional measures of efficacy (ie, effect on body weight, serum lipids, and blood pressure) will be evaluated to identify additional treatment effects of canagliflozin on comorbidities often seen in patients with T2DM.
At Week 26, in a subset of subjects (~25% of total subjects) who undergo a frequently sampled mixed-meal tolerance test (FS MMTT), to assess the effect of canagliflozin relative to placebo on:
• Post-prandial plasma glucose concentrations (including 2-hour PPG and glucose AUC)
• Measures of insulin secretion (including insulinogenic index, AUC C peptide/AUC glucose, and parameters of beta-cell sensitivity derived from a model based assessment of insulin secretion rate relative to glucose concentrations)
• Measures of insulin sensitivity using a minimal-model-based approach that accounts for UGE
|
|
| E.3 | Principal inclusion criteria |
• Man or woman ≥18 and ≤80 years of age with T2DM and currently treated with
metformin and an SU
• Meet the following HbA1c eligibility criteria:
HbA1c
Subjects Screening Visit Week -2 Visit
On metformin and an SU at protocol-specified
doses*a for at least 8 weeks prior to screening ≥7.0% and ≤10.5% n/a*b
On metformin and an SU, either or both at
doses below protocol-specified*a ≥7.5% ≥7.0% and ≤10.5%
*a= Metformin ≥2,000 mg/day (or ≥1,500 mg/day if intolerant of higher dose*b= If measured at screening more than 3 weeks prior to the Week -2 visit, obtain HbA1c at the Week -2 visit to assess inclusion criterion.
• FPG <270 mg/dL (15 mmol/L) at Week -2
Note: at the investigator’s discretion, based upon review of recent SMBG values,
subjects not meeting the Week -2 FPG criterion may return to the investigational site
within 7 days for a one-time repeat FPG and continue in the study if the subject’s
repeat FPG meets the criterion
• Site fasting fingerstick glucose of ≥110 mg/dL (6.1 mmol/L) and <270 mg/dL
(15 mmol/L) on Day 1
Note: at the investigator’s discretion, based upon review of recent SMBG values,
subjects not meeting the Day 1 criterion may return to the investigational site within
7 days for a one-time repeat fingerstick glucose and continue in the study if the
subject’s repeat fingerstick glucose meets the criterion
• Women must be:
– postmenopausal, defined as
◊ >45 years of age with amenorrhea for at least 18 months, or
◊ >45 years of age with amenorrhea for at least 6 months and <18 months and a
serum follicle stimulating hormone (FSH) level >40 IU/mL, or
– surgically sterile (have had a hysterectomy, bilateral oophorectomy, or tubal
ligation) or otherwise be incapable of pregnancy, or
– 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, and 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
– 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 must have a negative urine β-human chorionic
gonadotropin (β-hCG) pregnancy test at screening and baseline (predose, Day 1)
• 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
• To participate in the optional pharmacogenomic component of this study, subjects
must have signed the informed consent form for pharmacogenomic research
indicating willingness to participate in the pharmacogenomic component of the study
(where local regulations permit). Refusal to give consent for this component does not
exclude a subject from participation in the clinical study
• Adequate compliance with the run-in period study procedures, including performance
of the SMBG measurements (completed at least 3 or more SMBG measurements per
week) with appropriate diary entries, and ≥80% compliance (by pill count) with
single-blind placebo capsule |
|
| E.4 | Principal exclusion criteria |
• History of diabetic ketoacidosis, T1DM, pancreas or beta-cell transplantation, or
diabetes secondary to pancreatitis or pancreatectomy
• Repeated (ie, 2 or more over a 1-week period) FPG and/or fasting SMBG
measurements ≥270 mg/dL (15 mmol/L) during the pretreatment phase, despite
reinforcement of diet and exercise counseling
• Have proliferative diabetic retinopathy for which treatment is planned during the
course of the study
• History of 1 or more severe hypoglycemic episode within 6 months before screening.
Note: a severe hypoglycemic episode is defined as an event that requires the help of
another person (refer to Attachment 4, Hypoglycemia: Definitions, Symptoms, and
Treatment, for a definition of severe hypoglycemia)
• History of hereditary glucose-galactose malabsorption or primary renal glucosuria
• Ongoing, inadequately controlled thyroid disorder (eg, subject has a known thyroid
stimulating hormone [TSH] value that is either <0.2 or >10 mIU/L)
Note: subjects on thyroid hormone replacement therapy must be on stable doses for at least 6 weeks prior to Day 1
• On either a PPARγ agonist (eg, a thiazolidinedione [pioglitazone or rosiglitazone]) ongoing insulin therapy, another SGLT2 inhibitor, or any other AHA (including agents such as colesevelam and bromocriptine that have indications in some regions for treatment of T2DM) except as specified in the study inclusion criteria within 12 weeks before the screening visit
Note: subjects who have been treated with only a single dose of insulin may
participate.
• Ongoing eating disorder or significant weight loss or weight gain within 12 weeks
before the screening visit, defined as an increase or decrease of 5% in body weight
based upon clinic-based measurement or, if not available, subject report
• Renal disease that required treatment with immunosuppressive therapy or a history of dialysis or renal transplant
Note: subjects with a history of treated childhood renal disease, without sequelae,
may participate
• Myocardial infarction, unstable angina, revascularization procedure (eg, stent or
bypass graft surgery), or cerebrovascular accident within 3 months before screening,
or revascularization procedure is planned, or subject has a history of New York Heart
Association (NYHA) Class III-IV cardiac disease
• Findings on 12-lead ECG that would require urgent diagnostic evaluation or
intervention (eg, new clinically important arrhythmia or conduction disturbance)
• Uncontrolled hypertension (ie, using an average of 3 seated blood pressure readings with a diastolic blood pressure ≥100 mmHg or systolic blood pressure ≥160 mmHg) at Week -2
Note: subjects may have their blood pressure lowering medication regimen adjusted
and be re-evaluated to assess this criterion
• History of hepatitis B surface antigen or hepatitis C antibody positive (unless
associated with documented persistently stable/normal range aspartate
aminotransferase [AST] and ALT levels), or other clinically active liver disease
• History of prior bariatric surgical procedure within 3 years before the screening visit
Note: subjects with bariatric surgery more than 3 years before screening must be at a stable weight to be eligible to participate
• Estimated glomerular filtration rate (eGFR) <55 mL/min/1.73 m2 (or <60 mL/min/1.73 m2 if based upon restriction of metformin use in the metformin local label) or serum creatinine ≥1.4 mg/dL (124 µmol/L) for men and ≥1.3 mg/dL (115 µmol/L) for women
Note: a one-time repeat measurement is allowed, at the discretion of the investigator, if the values for serum creatinine/eGFR are not consistent with prior values
• Fasting serum triglycerides ≥600 mg/dL (6.74 mmol/L) at screening (or subsequent
visit if not fasting at screening)
Note: a one-time repeat of the serum triglycerides is allowed, at the discretion of the
investigator, if the screening value is not consistent with recent values
• Alanine aminotransferase level >2.0 times the ULN or total bilirubin >1.5 times the
ULN at screening (for elevations in bilirubin: if, in the opinion of the investigator and
agreed upon by the sponsor’s medical officer, the elevation in bilirubin is consistent
with Gilbert’s disease, the subject may participate)
• History of malignancy within 5 years before screening (exceptions: squamous and
basal cell carcinomas of the skin and carcinoma in situ of the cervix, 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)
• Clinically important hematologic disorder (eg, symptomatic anemia, proliferative
bone marrow disorder, thrombocytopenia)
• History of positive human immunodeficiency virus (HIV) antibody
• Investigator’s assessment that the subject’s life expectancy is less than 1 year...Refer to protocol page 59 for additional criteria |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint will be the change in HbA1c from baseline to Week 26. |
|
| 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 | No |
| 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 | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 38 |
| 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 | Information not present in EudraCT |
| 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 |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 14 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 14 |
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