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Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.

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Official Title

This study assesses the effects of twice-daily subcutaneous injection exenatide versus treatment with sulfonylurea (glimepiride) on long-term glycemic control and beta-cell function.

Exenatide Versus Glimepiride in Patients with Type 2 Diabetes

subcutaneous injection (5mcg or 10mcg), twice a day

oral tablet (titrated to maximally tolerated dose), once daily

Research Site

Long Term Treatment with Exenatide Versus Glimepiride in Patients with Type 2 Diabetes Pretreated with Metformin (EUREXA: European Exenatide Study)

Treatment failure is defined as one of the following:1. HbA1c exceeding 9% at any visit after the initial 3 months of treatment (i.e., earliest at Month 6), on the maximally tolerated dose of antidiabetic agents. 2. HbA1c exceeding 7% at 2 consecutive visits 3 months apart, after the initial 6 months of treatment (i.e., earliest at Month 9), on the maximally tolerated dose of antidiabetic agents.

Age Categorical

Age Continuous

Gender, Male/Female

Glycosylated hemoglobin (HbA1c)

Study Specific Characteristic

Weight

Only patients who reached primary endpoint 12 months or more before the projected end of the study could enter period III.

Number of patients with treatment failure

Number of patients censored

The null hypothesis (H0) and alternative hypothesis (H1) for the primary analysis (i.e., non-inferiority) are:H0: hazards of treatment for Exenatide/hazards of treatment for Glimepiride >=1.25.H1: hazards of treatment for Exenatide/hazards of treatment for Glimepiride < 1.25. With 527 patients in each arm, the study would have approximately 90% power to conclude non-inferiority of Exenatide to Glimepiride.

ITT Efficacy Population: Enrolled patients with a baseline and at least one post-baseline measurement of HbA1c in Study Period II (including only Study Period II); patients analyzed according to treatment as randomized.

Number of Patients with treatment failure

Kaplan-Meier survival curves for time to treatment failure were compared between treatment groups using log rank test.

Time to treatment failure

HOMA-B at Year 3. HOMA-B is an index of beta-cell function and was calculated as: HOMA-B = (20 x fasting insulin (measured in pmol/L))/((fasting glucose (measured in mmol/L) - 3.5) x 7.175).

Mixed-model Repeated Measures (MMRM) analysis includes treatment, visit, and treatment by visit interaction, and baseline value as a covariate. The unstructured covariance matrix was used.

ITT Efficacy Population. The analysis included only time points up to that week where at least 25% of the originally enrolled population was still in the study. Missing data at Year 3 was not imputed.

Homeostasis Model Assessment of Beta-cell Function (HOMA-B) at Year 3

Change in HOMA-B from baseline to endpoint.

Change in HOMA-B from baseline to endpoint was analyzed by an analysis of covariance (ANCOVA) model that includes treatment and baseline HbA1c stratum (<=7.3%, >7.3% to <=8.2%, >8.2%) as factors and baseline value as a covariate.

ITT Efficacy Population. Missing data at endpoint was imputed using last observation carried forward (LOCF) approach.

Change in HOMA-B from baseline to endpoint

Fasting proinsulin (measured in pmol/L)/insulin (measured in pmol/L)  ratio at Year 3.

MMRM analysis includes treatment, visit, and treatment by visit interaction, and baseline value as a covariate. The unstructured covariance matrix was used.

Fasting proinsulin/insulin ratio at Year 3

Change in fasting proinsulin (measured in pmol/L)/insulin (measured in pmol/L) ratio from baseline to endpoint.

Change in fasting proinsulin/insulin ratio from baseline to endpoint was analyzed by an ANCOVA model that includes treatment and baseline HbA1c stratum (<=7.3%, >7.3% to <=8.2%, >8.2%) as factors and baseline value as a covariate.

ITT Efficacy Population. Missing data at endpoint was imputed using LOCF approach.

Change in fasting proinsulin/insulin ratio from baseline to endpoint.

DI30/DG30 at Year 3. DI30/DG30 ratio was calculated as (30 minute post prandial insulin - fasting insulin) (measured in pmol/L)/(30 minute post prandial glucose - fasting glucose) (measured in mmol/L).

Ratio of the 30 minute increment in plasma insulin concentration and the 30 minute increment in plasma glucose during the oral glucose tolerance test (DI30/DG30 ratio) at Year 3

Change in DI30/DG30 ratio from baseline to endpoint.

Change in DI30/DG30 ratio from baseline to endpoint was analyzed by an ANCOVA model that includes treatment and baseline HbA1c stratum (<=7.3%, >7.3% to <=8.2%, >8.2%) as factors and baseline value as a covariate.

Change in DI30/DG30 ratio from baseline to endpoint

Disposition Index at Year 3. Disposition index was calculated as (DI30/DG30 ratio)/(HOMA index for insulin resistance (HOMA-IR)); where HOMA-IR=(fasting insulin (measured in pmol/L) x fasting glucose (measured in mmol/L))/(22.5 x 7.175).

Disposition index at Year 3

Change in disposition index from baseline to endpoint.

Change in disposition index from baseline to endpoint was analyzed by an ANCOVA model that includes treatment and baseline HbA1c stratum (<=7.3%, >7.3% to <=8.2%, >8.2%) as factors and baseline value as a covariate.

Change in disposition index from baseline to endpoint

Change in HbA1c from baseline to Year 3

Change in HbA1c from baseline to endpoint. Endpoint for HbA1c was defined as the HbA1c measured at the treatment failure for patients reaching primary endpoint and was the last observation in study period II for other patients (either followed until the end of the study period II or discontinuing the study).

Change in HbA1c from baseline to endpoint was analyzed by an ANCOVA model that includes treatment as factor and baseline value as a covariate.

Change in HbA1c from baseline to endpoint

MMRM includes treatment, visit, and treatment by visit interaction, and baseline value as a covariate. The unstructured covariance matrix was used.

Fasting plasma glucose at Year 3

Change in fasting plasma glucose from baseline to endpoint.

Change in fasting plasma glucose from baseline to endpoint was analyzed by an ANCOVA model that includes treatment and baseline HbA1c stratum (<=7.3%, >7.3% to <=8.2%, >8.2%) as factors and baseline value as a covariate.

Change in fasting plasma glucose from baseline to endpoint

Postprandial (2 hours) plasma glucose at Year 3.

Postprandial (2 hours) plasma glucose at Year 3

Change from baseline in postprandial (2 hours) plasma glucose to endpoint.

Change in postprandial (2 hours) plasma glucose from baseline to endpoint was analyzed by an ANCOVA model that includes treatment and baseline HbA1c stratum (<=7.3%, >7.3% to <=8.2%, >8.2%) as factors and baseline value as a covariate.

Change in postprandial (2 hours) plasma glucose from baseline to endpoint

Change in Body weight from baseline to Year 3.

MMRM analysis includes treatment, visit, and treatment by visit interaction and baseline value as a covariate. The unstructured covariance matrix was used.

ITT Safety Population: Enrolled patients receiving at least one dose of study medication in Study Period II with patients analyzed according to treatment actually received. The analysis included only time points up to that week where at least 25% of the originally enrolled population was still in the study. Missing data at Year 3 was not imputed.

Change in Body weight from baseline to Year 3

ITT Safety Population. The analysis included only time points up to that week where at least 25% of the originally enrolled population was still in the study. Missing data at Year 3 was not imputed.

Systolic Blood pressure at Year 3

Diastolic Blood pressure at Year 3

MMRM analysis includes treatment, visit, and visit by treatment interaction, and baseline value as a covariate. The unstructured covariance matrix was used.

Heart rate at Year 3

Triglycerides at Year 3

Total Cholesterol at Year 3

High-density Lipoprotein (HDL) Cholesterol at Year 3

All hypoglycemia episodes were taken into account. Severe hypoglycemia: event requiring assistance of another person to administer carbohydrate, glucagons, or other resuscitative actions; Documented symptomatic hypoglycemia: event with typical symptoms accompanied by a measured plasma glucose concentration <=70 mg/dL; Asymptomatic hypoglycemia: event not accompanied by typical symptoms but with a measured plasma glucose concentration <=70 mg/dL; Probable symptomatic hypoglycemia: event with symptoms not accompanied by a plasma glucose determination.

The number of hypoglycemic episodes by patient were compared between treatment groups using a negative binomial model with effects for treatment and baseline HbA1c and the logarithm of the days of exposure as the offset variable.

Hypoglycemia Rate Per Year

MMRM analysis includes treatment, visit, and treatment by visit interaction, and baseline value at Period III as a covariate. The compound symmetric covariance structure was assumed.

Extension ITT Efficacy Population: Extension enrolled patients with at least one post-baseline measurement of HbA1c in Study Period III. The analysis included patients randomized at entry in study period III. Missing data at Year 2 was not imputed.

Change in HbA1c from baseline to Year 2 for patients randomized at entry in Period III

Extension ITT Efficacy population. The analysis included patients not randomized at entry in study period III. Missing data at Year 2 was not imputed.

Change in HbA1c from baseline to Year 2 for patients not randomized at entry in Period III

Extension ITT Safety Population: Extension enrolled patients receiving at least one dose of study medication in Study Period III.

Hypoglycemia Rate Per Year in Period III

Period II

Period III

Period I

Patients meeting defined failure of HbA1c control (primary
endpoint) in Study Period II were eligible for entry to Study Period III

Arms	Assigned Interventions
Experimental: Exenatide	Drug: exenatide subcutaneous injection (5mcg or 10mcg), twice a day Other Name: Byetta
Active Comparator: Glimepiride	Drug: glimepiride oral tablet (titrated to maximally tolerated dose), once daily Other Name: Amaryl

Exenatide Versus Glimepiride in Patients with Type 2 Diabetes

Official Title

Medical condition

Phase

Healthy volunteers

Study drug

Sex

Actual Enrollment

Study type

Age

Date

Study design

Verification:

Sponsors

Collaborators

Inclusion Criteria

Exclusion Criteria

Documents available

Trial Results Summaries

Contacts

Contact

Investigators

Principal Investigator