A Randomized, Double-Blind, Placebo-Controlled, 3-Arm, Parallel-Group, 26-Week Multicenter Study with a 26-Week Extension to Evaluate the Efficacy, Safety, and Tolerability of JNJ-28431754 (Canagliflozin) Compared with Placebo in the Treatment of Subjects With Type 2 Diabetes Mellitus With Inadequate Glycemic Control on Metformin and Pioglitazone Therapy - CANTATA-MP

• Conditions: Type 2 Diabetes Mellitus with inadeguate glycemic control; MedDRA version: 9.1Level: LLTClassification code 10045242

• Registration Number: EUCTR2009-018070-64-IT
• Lead Sponsor: JANSSEN CILAG INTERNATIONAL NV

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2010-07-26
• Last Update Posted: 18 September 2012

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 360

Inclusion Criteria

Potential subjects must satisfy all of the following criteria at screening, or at the indicated visits, to be enrolled in the study: • Man or woman =18 and =80 years of age with T2DM who meets 1 of the following 5 criteria: - On dual combination metformin and pioglitazone, both agents at protocol-specified doses* (stable doses for at least 16 weeks prior to screening), with an HbA1c of =7.0% and =10.5% at screening (or at Week -2, if screening measurement is more than 3 weeks prior to Week -2) or - On dual combination metformin and pioglitazone (stable doses for at least 8 weeks prior to screening), with either agent at a dose below protocol-specified*, with an HbA1c of =7.5 % and =11.0% at screening, and has an HbA1c of =7.0% and =10.5% at Week -2, after at least 8 weeks on stable protocol-specified* doses of metformin and pioglitazone or - On dual combination metformin and rosiglitazone, with an HbA1c of =7.0% and =10.5% at screening (stable doses for at least 8 weeks prior to screening), and has an HbA1c of =7.0% and =10.5% at Week -2, after at least 8 weeks on stable protocol-specified* doses of metformin and pioglitazone Canagliflozin: Clinical Protocol 28431754DIA3012 FINAL - 08 January 2010 55 or - On a PPAR? agent (pioglitazone or rosiglitazone) in dual combination with another oral AHA, with an HbA1c of =7.0% and =10.5% at screening (stable doses for at least 8 weeks prior to screening), and has an HbA1c of =7.0% and =10.5% at Week -2, after at least 8 weeks on stable protocol-specified* doses of metformin and pioglitazone or - On metformin, a PPAR? agent (pioglitazone or rosiglitazone), and an SU or a DPP-4 inhibitor in triple combination therapy with an HbA1c of =6.5% and =9.5% at screening (stable doses for at least 8 weeks prior to screening), and has an HbA1c of =7.0% and =10.5% at Week -2, after at least 8 weeks on stable protocolspecified* doses of metformin and pioglitazone *Protocol-specified doses = metformin =2,000 mg per day (or =1,500 mg per day, if unable to tolerate a higher dose) and pioglitazone 30 mg or 45 mg per day. • FPG <270 mg/dL (15 mmol/L) at Week -2. • Site fasting fingerstick glucose of =110 mg/dL (6.1 mmol/L) and <270 mg/dL (15 mmol/L) on Day 1. • 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 Canagliflozin: Clinical Protocol 28431754DIA3012 FINAL - 08 January 2010 56 methods for subjects participating in clinical trials, for the duration of their participation in the study, or – not heterosexually active. • Women of childbearing potential must have a negative urine ß-human chorionic gonadotropin (ß-hCG) pregnancy test at screening and baseline (predose, Day 1). • Willing and able to adhere to the prohibitions and restri

Exclusion Criteria

Diabetes-related or Metabolic • History of diabetic ketoacidosis, T1DM, pancreas or ß-cell transplantation, or diabetes secondary to pancreatitis or pancreatectomy • Repeated (ie, 2 or more over a 1-week period) FPG and/or fasting SMBG glucose measurements =270 mg/dL during the pre-treatment 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. • History of hereditary glucose-galactose malabsorption or primary renal glucosuria Canagliflozin: Clinical Protocol 28431754DIA3012 FINAL - 08 January 2010 57 • Ongoing, inadequately controlled thyroid disorder (eg, thyroid stimulating hormone [TSH] value <0.2 or >10 mIU/L); • Required ongoing insulin therapy within 12 weeks prior to the screening visit • Ongoing eating disorder or significant weight loss or weight gain within 12 weeks, defined as an increase or decrease of 5% in body weight based upon clinic-based measurement or, if not available, subject report Renal/Cardiovascular • Renal disease that required treatment with immunosuppressive therapy or a history of dialysis or renal transplant. • 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 (refer to Attachment 3, New York Heart Association Classification of Cardiac Disease, for a description of the classes). • 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. Gastrointestinal • 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. Laboratory • Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 or serum creatinine =1.4 mg/dL (124 µmol/L) for men and =1.3 mg/dL (115 µmol/L) for women • Fasting serum triglycerides =600 mg/dL (6.74 mmol/L) at screening (or subsequent visit if not fasting at screening). • 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) Other conditions • 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 human immunodeficiency

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Secondary Objective: After 26 weeks of treatment, to assess the effect of canagliflozin relative to placebo on: Fasting plasma glucose (FPG); Body weight; Proportion of subjects with HbA1c <7.0% and <6.5% ; Fasting plasma lipids; Fasting measures of beta cell function; Systolic and diastolic blood pressure; Time to rescue therapy and proportion of subjects receiving rescue therapy After 52 weeks of treatment, to assess the effect of canagliflozin relative to baseline on: Glycemic control; Body weight; Proportion of subjects with HbA1c <7.0% and <6.5%; Fasting plasma lipids; Fasting measures of beta cell function; Systolic and diastolic blood pressure; Time to rescue therapy and proportion of subjects receiving rescue therapy;Main Objective: To assess the effect of canagliflozin relative to placebo on hemoglobin A1c (HbA1c) after 26 weeks of treatment • To assess the safety and tolerability of canagliflozin;Primary end point(s): Efficacy endpoint: change in HbA1c from baseline to Week 26.