Insulin Degludec Once Daily Similar to Insulin Glargine
Insulin Degludec Once Daily Similar to Insulin Glargine
This phase 3a, 26-week, randomized, controlled, open-label, multinational, treat-to-target, noninferiority trial compared efficacy and safety between IDeg 200 units/mL and IGlar, both administered once daily in combination with metformin with or without a DPP-4 inhibitor in insulin-naïve participants with T2DM previously treated with oral antidiabetic drugs, who qualified for intensification of treatment. The trial was open-label because of the lack of availability of appropriate placebo-containing injection devices. The trial was conducted between 1 March and 26 November 2010 at 106 sites in 8 countries (Canada, France, Ireland, the Russian Federation, South Africa, Ukraine, the U.K., and the U.S.).
The study was completed in compliance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice Guidelines; institutional review boards reviewed and approved the protocol for each study site; and all patients provided written, informed consent before participation in the trial. The trial is registered at ClinicalTrials.gov as NCT01068665.
Candidates who were insulin-naïve adults with T2DM for ≥6 months, HbA1c 7–10% (53–86 mmol/mol, inclusive), BMI ≤45 kg/m, and previous treatment with metformin with or without additional oral antidiabetic drugs for ≥3 months were eligible to participate in the study. Key exclusion criteria included thiazolidinedione, exenatide, or liraglutide use within 3 months of participation in the trial, cardiovascular disease (e.g., stroke, myocardial infarction, unstable angina pectoris) within 6 months of the trial, uncontrolled hypertension (systolic blood pressure ≥180 mmHg or diastolic blood pressure ≥100 mmHg), impaired liver function (alanine aminotransferase ≥2.5 times the upper limit of normal), impaired renal function (serum creatinine ≥125 μmol/L or ≥1.4 mg/dL for males and ≥110 μmol/L or ≥1.3 mg/dL for females), recurrent severe hypoglycemia (more than one episode requiring assistance in the previous 12 months) or hypoglycemic unawareness, hospitalization for diabetic ketoacidosis within 6 months of the trial, and proliferative retinopathy or maculopathy.
IDeg 200 units/mL was administered once-daily with the main evening meal and, consistent with its product labeling, IGlar was administered once daily at the same time each day. Insulin treatments were injected subcutaneously in the thigh, upper arm, or abdomen. The starting dose for each insulin was 10 units and, during the treatment period, the dose was systematically titrated using a treat-to-target approach striving for a prebreakfast self-measured blood glucose (SMBG) level of <5 mmol/L (<90 mg/dL). Both IDeg 200 units/mL and IGlar were titrated once weekly (Supplementary Table 1) according to the average of three preceding prebreakfast SMBG levels and other available data (e.g., symptoms of hypoglycemia or hyperglycemia, previous responses to dose adjustments, and any additional nonmandatory blood glucose measurements). The treatment period was 26 weeks, and doses were individually titrated in an effort to achieve a specific target of <5 mmol/L (<90 mg/dL) with both treatments. After the 26-week treatment period, participants switched their basal insulin treatment to the intermediate-acting NPH insulin for 1 week to wash out the investigational exogenous insulins and minimize interference with insulin antibody measurements.
The safety committee from the sponsor performed ongoing blinded safety surveillance. Titration of insulin doses was monitored by the outside company Quintiles (Singapore, U.S., and Switzerland) and reviewed by the sponsor's titration committee. Cardiovascular events were adjudicated and assessed by an independent external event adjudication committee.
The primary end point for this study was change in HbA1c from baseline after 26 weeks of treatment. Secondary confirmatory end points tested were number of treatment-emergent confirmed hypoglycemic episodes, change from baseline in central laboratory–measured fasting plasma glucose (FPG), within-subject variability as measured by coefficient of variation, and frequency of participants achieving HbA1c <7% (<53 mmol/mol) without confirmed hypoglycemic episodes. The supportive secondary end points included 9-point SMBG profiles, frequency of participants achieving HbA1c <7% (<53 mmol/mol), and Health-Related Quality of Life (Short Form 36) questionnaire scores. The safety assessments included adverse events (AEs), hypoglycemic episodes, insulin dose, body weight, physical examination, vital signs, fundoscopy, electrocardiogram, and laboratory tests (including antibodies). Confirmed hypoglycemic episodes were defined as episodes of SMBG of <3.1 mmol/L (<56 mg/dL) or severe episodes requiring assistance. Hypoglycemic episodes occurring between 0001 and 0559 h (inclusive) were classified as nocturnal.
Laboratory analyses were performed by Quintiles Central Laboratories in Scotland, South Africa, and the U.S. Insulin antibodies were analyzed at Celerion Switzerland AG (Fehraltorf, Switzerland).
Analyses of all efficacy end points were based on the full analysis set, which included all randomized participants. The safety analysis set included all participants who received at least one dose of the investigational product or the comparator. Missing values were imputed with the last observation carried forward method.
The primary objective of this trial was to confirm the noninferiority of IDeg 200 units/mL once daily to IGlar once daily as assessed by change in HbA1c from baseline after 26 weeks of treatment. Type I error was controlled by adopting a hierarchical (fixed-sequence) testing procedure for selected end points, including change in HbA1c, number of confirmed hypoglycemic episodes, change in FPG, within-subject variability in prebreakfast blood glucose, and responders without hypoglycemic episodes. Noninferiority was confirmed if the upper limit of the 95% CI for the treatment difference was ≤0.4%. Sample size was determined on the basis of the primary objective with a t statistic under the assumption of a one-sided t test of size 2.5%, a zero mean treatment difference, and a 1.3% SD for HbA1c.
Treatment difference in change from baseline in HbA1c after 26 weeks was analyzed with an ANOVA model with treatment, antidiabetic therapy at screening, sex, and region (Europe, North America, or South Africa) as fixed factors and age and baseline HbA1c as covariates. Treatment differences in FPG, Health-Related Quality of Life (Short Form 36) score, body weight, and insulin dose (log transformed) at the end of trial were analyzed by means of ANOVA with treatment, antidiabetic therapy at screening, sex, and region as fixed factors and age and relevant baseline values as covariates. A mixed-effects model was fitted to the 9-point SMBG profile data, which included treatment, time, interaction between treatment and time, antidiabetic therapy at screening, sex, and region as fixed factors; age as covariate; and subject as a random factor. Logarithm-transformed SMBG prebreakfast values were analyzed as repeated measures in a linear mixed model with treatment, antidiabetic therapy at screening, sex, and region as fixed factors; age as covariate; and subject as random factor. The model assumed independent within- and between-subject errors, with variances depending on treatment. The within-subject coefficient of variation was derived from the estimated within-subject variability (σ) as square root (exp(σ) – 1). Responder (HbA1c) analysis was based on a logistic regression model using treatment, antidiabetic therapy at screening, sex, and region as fixed factors and age and baseline HbA1c as covariates. The number of treatment-emergent confirmed hypoglycemic episodes was analyzed according to a negative binomial regression model including treatment, antidiabetic therapy at screening, sex, and region as fixed factors and age as covariate. A similar model was used for post hoc analysis of treatment-emergent confirmed hypoglycemic episodes in participants requiring ≥60 and ≥80 units of insulin by the end of the trial; however, nocturnal confirmed hypoglycemic episodes for participants requiring ≥80 units by the end of trial were analyzed by mean of a Poisson model with only treatment as a fixed factor.
Research Design and Methods
Trial Design
This phase 3a, 26-week, randomized, controlled, open-label, multinational, treat-to-target, noninferiority trial compared efficacy and safety between IDeg 200 units/mL and IGlar, both administered once daily in combination with metformin with or without a DPP-4 inhibitor in insulin-naïve participants with T2DM previously treated with oral antidiabetic drugs, who qualified for intensification of treatment. The trial was open-label because of the lack of availability of appropriate placebo-containing injection devices. The trial was conducted between 1 March and 26 November 2010 at 106 sites in 8 countries (Canada, France, Ireland, the Russian Federation, South Africa, Ukraine, the U.K., and the U.S.).
The study was completed in compliance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice Guidelines; institutional review boards reviewed and approved the protocol for each study site; and all patients provided written, informed consent before participation in the trial. The trial is registered at ClinicalTrials.gov as NCT01068665.
Participants
Candidates who were insulin-naïve adults with T2DM for ≥6 months, HbA1c 7–10% (53–86 mmol/mol, inclusive), BMI ≤45 kg/m, and previous treatment with metformin with or without additional oral antidiabetic drugs for ≥3 months were eligible to participate in the study. Key exclusion criteria included thiazolidinedione, exenatide, or liraglutide use within 3 months of participation in the trial, cardiovascular disease (e.g., stroke, myocardial infarction, unstable angina pectoris) within 6 months of the trial, uncontrolled hypertension (systolic blood pressure ≥180 mmHg or diastolic blood pressure ≥100 mmHg), impaired liver function (alanine aminotransferase ≥2.5 times the upper limit of normal), impaired renal function (serum creatinine ≥125 μmol/L or ≥1.4 mg/dL for males and ≥110 μmol/L or ≥1.3 mg/dL for females), recurrent severe hypoglycemia (more than one episode requiring assistance in the previous 12 months) or hypoglycemic unawareness, hospitalization for diabetic ketoacidosis within 6 months of the trial, and proliferative retinopathy or maculopathy.
Treatments
IDeg 200 units/mL was administered once-daily with the main evening meal and, consistent with its product labeling, IGlar was administered once daily at the same time each day. Insulin treatments were injected subcutaneously in the thigh, upper arm, or abdomen. The starting dose for each insulin was 10 units and, during the treatment period, the dose was systematically titrated using a treat-to-target approach striving for a prebreakfast self-measured blood glucose (SMBG) level of <5 mmol/L (<90 mg/dL). Both IDeg 200 units/mL and IGlar were titrated once weekly (Supplementary Table 1) according to the average of three preceding prebreakfast SMBG levels and other available data (e.g., symptoms of hypoglycemia or hyperglycemia, previous responses to dose adjustments, and any additional nonmandatory blood glucose measurements). The treatment period was 26 weeks, and doses were individually titrated in an effort to achieve a specific target of <5 mmol/L (<90 mg/dL) with both treatments. After the 26-week treatment period, participants switched their basal insulin treatment to the intermediate-acting NPH insulin for 1 week to wash out the investigational exogenous insulins and minimize interference with insulin antibody measurements.
The safety committee from the sponsor performed ongoing blinded safety surveillance. Titration of insulin doses was monitored by the outside company Quintiles (Singapore, U.S., and Switzerland) and reviewed by the sponsor's titration committee. Cardiovascular events were adjudicated and assessed by an independent external event adjudication committee.
Primary and Secondary End Points
The primary end point for this study was change in HbA1c from baseline after 26 weeks of treatment. Secondary confirmatory end points tested were number of treatment-emergent confirmed hypoglycemic episodes, change from baseline in central laboratory–measured fasting plasma glucose (FPG), within-subject variability as measured by coefficient of variation, and frequency of participants achieving HbA1c <7% (<53 mmol/mol) without confirmed hypoglycemic episodes. The supportive secondary end points included 9-point SMBG profiles, frequency of participants achieving HbA1c <7% (<53 mmol/mol), and Health-Related Quality of Life (Short Form 36) questionnaire scores. The safety assessments included adverse events (AEs), hypoglycemic episodes, insulin dose, body weight, physical examination, vital signs, fundoscopy, electrocardiogram, and laboratory tests (including antibodies). Confirmed hypoglycemic episodes were defined as episodes of SMBG of <3.1 mmol/L (<56 mg/dL) or severe episodes requiring assistance. Hypoglycemic episodes occurring between 0001 and 0559 h (inclusive) were classified as nocturnal.
Laboratory analyses were performed by Quintiles Central Laboratories in Scotland, South Africa, and the U.S. Insulin antibodies were analyzed at Celerion Switzerland AG (Fehraltorf, Switzerland).
Statistical Analysis
Analyses of all efficacy end points were based on the full analysis set, which included all randomized participants. The safety analysis set included all participants who received at least one dose of the investigational product or the comparator. Missing values were imputed with the last observation carried forward method.
The primary objective of this trial was to confirm the noninferiority of IDeg 200 units/mL once daily to IGlar once daily as assessed by change in HbA1c from baseline after 26 weeks of treatment. Type I error was controlled by adopting a hierarchical (fixed-sequence) testing procedure for selected end points, including change in HbA1c, number of confirmed hypoglycemic episodes, change in FPG, within-subject variability in prebreakfast blood glucose, and responders without hypoglycemic episodes. Noninferiority was confirmed if the upper limit of the 95% CI for the treatment difference was ≤0.4%. Sample size was determined on the basis of the primary objective with a t statistic under the assumption of a one-sided t test of size 2.5%, a zero mean treatment difference, and a 1.3% SD for HbA1c.
Treatment difference in change from baseline in HbA1c after 26 weeks was analyzed with an ANOVA model with treatment, antidiabetic therapy at screening, sex, and region (Europe, North America, or South Africa) as fixed factors and age and baseline HbA1c as covariates. Treatment differences in FPG, Health-Related Quality of Life (Short Form 36) score, body weight, and insulin dose (log transformed) at the end of trial were analyzed by means of ANOVA with treatment, antidiabetic therapy at screening, sex, and region as fixed factors and age and relevant baseline values as covariates. A mixed-effects model was fitted to the 9-point SMBG profile data, which included treatment, time, interaction between treatment and time, antidiabetic therapy at screening, sex, and region as fixed factors; age as covariate; and subject as a random factor. Logarithm-transformed SMBG prebreakfast values were analyzed as repeated measures in a linear mixed model with treatment, antidiabetic therapy at screening, sex, and region as fixed factors; age as covariate; and subject as random factor. The model assumed independent within- and between-subject errors, with variances depending on treatment. The within-subject coefficient of variation was derived from the estimated within-subject variability (σ) as square root (exp(σ) – 1). Responder (HbA1c) analysis was based on a logistic regression model using treatment, antidiabetic therapy at screening, sex, and region as fixed factors and age and baseline HbA1c as covariates. The number of treatment-emergent confirmed hypoglycemic episodes was analyzed according to a negative binomial regression model including treatment, antidiabetic therapy at screening, sex, and region as fixed factors and age as covariate. A similar model was used for post hoc analysis of treatment-emergent confirmed hypoglycemic episodes in participants requiring ≥60 and ≥80 units of insulin by the end of the trial; however, nocturnal confirmed hypoglycemic episodes for participants requiring ≥80 units by the end of trial were analyzed by mean of a Poisson model with only treatment as a fixed factor.
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