A Randomized Phase 2, Double-blind, Placebo-controlled, Treat-to-Target, Parallel-group, 3-arm, Multicenter Study to Assess the Efficacy and Safety of Canagliflozin as Add-on Therapy to Insulin in the Treatment of Subjects with Type 1 Diabetes Mellitus
Description
Detailed Description
Canagliflozin (CANA) is an oral antihyperglycemic agent (AHA) approved for the treatment of subjects with Type 2 Diabetes Mellitus (T2DM). In subjects with T2DM, CANA lowers blood glucose by an insulin-independent mechanism and has an intrinsic low risk of hypoglycemia. In subjects with T1DM the addition of CANA to intensive insulin therapy is expected to lead to less insulin requirement which is expected to lead to a reduced insulin dose requirement, weight gain, glucose variability and low the risk of hypoglycemia. The primary objective of this study is to assess the effect of CANA 100 mg and 300 mg compared with placebo on the change in HbA1c and body weight after 18 weeks of treatment. This is a randomized, double-blind, placebo-controlled, parallel-group, multicenter, interventional study of CANA in male and female subjects between the ages of 25 years to 65 years, inclusive, with a diagnosis of T1DM for at least 1 year, and inadequate glycemic control (ie, HbA1c of 7.0% to 9.0%) on basal plus bolus insulin at screening. Approximately 330 subjects will be randomly assigned in this study (20 at the USC site), with approximately 110 subjects randomized per treatment group. The primary hypothesis will be assessed using a composite primary endpoint: proportion of subjects with HbA1c reduction 0.4% and no increase in body weight. Assuming the proportion of subjects meeting the composite criteria is 20% for placebo and 40% for each CANA dose, and assuming a 2-sided family-wise Type I error rate of 0.05, it is estimated that a sample size of 100 randomized subjects per group will be required to achieve 84% power for the comparison of each CANA dose to placebo. A modestly larger sample size (110 subjects per arm) will be randomized to each treatment arm. The modified intent-to-treat (mITT) analysis set includes all randomized subjects who have received at least 1 dose of double-blind study medication. The per-protocol (PP) analysis set consists of all mITT subjects who complete the 18-week double-blind treatment phase, and have no major protocol deviations that may affect the interpretation of the primary efficacy endpoint. The completers analysis set consists of all mITT subjects who complete the 18-week double blind treatment period. The primary efficacy endpoint will be proportion of subjects with HbA1c reduction 0.4% and no increase in body weight after 18 weeks of treatment. The primary efficacy endpoint will be analyzed longitudinally using a generalized linear mixed model. The model will include the fixed, categorical effects of treatment, stratification factor (use of CSII vs MDI), visit, and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline HbA1c, baseline body weight, and baseline-by-visit interactions. An unstructured covariance will be used to model the within-patient errors. The odds ratio and 2-sided 95% confidence interval (CI) for the treatment comparison at Week 18 (CANA vs placebo) will be estimated based on this model. As a sensitivity analysis, the last-observation-carried-forward method will be applied when the Week 18 values are missing. The odds ratio will be assessed by a logistic regression model with terms for baseline HbA1c, baseline body weight, treatment and stratification factor.
Phase
N/AInclusion and Exclusion Criteria
- Must have type 1 diabetes mellitus (T1DM) for at least 1 year
- Must have have inadequate glycemic control (as defined by glycosylated hemoglobin level of >= 7.0% to <= 9.0%) on basal plus bolus insulin at screening
- Must have body mass index 21 to 35 kg/m2 inclusive
- Must be on a total daily dose of insulin >= 0.6 IU/kg at screening
- Must be on a stable insulin regimen for at least 8 weeks prior to screening
- History of T2DM, pancreas or β-cell transplantation, or diabetes secondary to pancreatitis or pancreatectomy
- Severe hypoglycemia (defined as an event required assistance from another person, or which resulted in seizure or loss of consciousness) within 6 months prior to study start
- Diabetic ketoacidosis within 6 months prior to study start
- History of hereditary glucose-galactose malabsorption or primary renal glycosuria
- An ongoing, inadequately controlled thyroid disorder
Sites
Please contact Valerie Ruelas to learn more about where you can participate in this trial. Please use the contact form on the right side.
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