Avandia™ + Amaryl™ or Avandamet™ Compared With Metformin (AVALANCHE™ Study)

Phase 3

Completed

Conditions: Type 2 Diabetes Mellitus

Interventions: Drug: Avandia and Amaryl
Drug: Avandamet
Drug: Metformin

Registration Number: NCT00131664

Lead Sponsor: Canadian Heart Research Centre

Brief Summary: The incidence of type 2 diabetes is on the increase. According to recent Canadian Diabetes Association guidelines glucose control, based on the A1C measurement, needs to be achieved within a 6-12 month period of time after the initial diagnosis of type 2 diabetes. The guidelines on the use of antihyperglycemic agents identify the potential benefits of sub-maximal oral combination therapy in order to achieve more rapid and improved glycemic control compared with higher dose monotherapy. Furthermore, many patients on prolonged oral antihyperglycemic monotherapy who then start on combination therapy may not achieve the required target glycemic control. Indeed early initiation of combination therapies may be necessary to achieve and maintain glycemic targets because of the progressive deterioration of pancreatic β cell function and glycemic control.

Detailed Description: AvandametTM combines two oral antihyperglycemic agents, rosiglitazone maleate and metformin hydrochloride, with different but complementary mechanisms of action to improve glycemic control while reducing circulating insulin levels in patients with type 2 diabetes. AvandiaTM and AmarylTM combine two antidiabetic agents, rosiglitazone maleate and glimepiride. Glimepiride is an effective antihyperglycemic agent which has a low incidence of hypoglycemia, symptomatic hypoglycemia, severe hypoglycemia, and confirmed hypoglycemia. Subjects in this study who are inadequately controlled on diet, exercise and a submaximal dose of metformin or sulfonylurea (SU) will be randomized to either a combination of metformin plus rosiglitazone (AvandametTM) or a combination of AvandiaTM + AmarylTM or a Metformin monotherapy arm. As per the Canadian Diabetes Association (CDA) guidelines, their fasting plasma glucose and A1C to be 7 (mmol/L / percent) or less throughout the study. If the subject does not achieve the target then either AvandametTM or AvandiaTM and AmarylTM or Metformin will be up-titrated in an effort to reach this CDA recommended target. This study will attempt to demonstrate that the either combination arm of rosiglitazone plus metformin (AvandametTM) or the other combination arm of AvandiaTM + AmarylTM will provide greater glycemic control while avoiding the side-effects associated with the use of maximal dose metformin.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 391

Inclusion Criteria

Type 2 diabetes patients
18 - 75 years old
Type 2 diabetes mellitus (DM) drug naïve or on submaximal oral monotherapy < 3 years
A1C criteria at screening:
1. 7.1-10% for drug naïve patients after failure of diet control and life-style modification
2. 7.1 - 9% on single therapy (e.g. not more 10 mg of Glyburide or 4 mg of Amaryl™ or 1000mg of Metformin) who will start after 2 weeks wash-out. During wash out the following will be done: i) diet and life style modification ii) Angiotensin converting enzyme inhibitor (ACE), aspirin (80 mg), and statin if appropriate
Signed informed consent

Exclusion Criteria

Type 1 diabetes
Subjects currently treated with insulin
Subject treated for previous 3 month with any thiazolidinedione (TZD)
Evidence of clinically significant concomitant illnesses which are not controlled by medication and/or may limit participation in the study as judged by the investigator
Subjects who have hypersensitivity to any components of study drugs
Participation in a clinical trial and/or intake of an investigational drug within 30 days prior to screening.
Pregnant or nursing females
Females of childbearing potential who are not on adequate birth control
Liver enzymes (Alanine Aminotransferase (ALT) > 2.5 times upper limit of normal)
Renal impairment: serum creatinine ≥ 136umol/L (males) and ≥ 124 umol/L (females)
Congestive Heart Failure (CHF class III/IV)
Weight >160 kg

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Avandia and Amaryl	Avandia and Amaryl	Avandia + Amaryl 4 mg + 1 mg once daily titration up to 8 mg + 2 mg once daily over 6 months
Avandamet	Avandamet	Avandamet 2 mg / 500 mg twice daily titration up to 4 mg / 1000 mg twice daily over 6 months
Metformin	Metformin	Metformin 500 mg twice daily titration up to 1000 mg twice daily over 6 months

Primary Outcome Measures

Name	Time	Method
Mean Change From Baseline in A1C at Month 6	Baseline and Month 6	Change from baseline was calculated as the Month 6 value minus the baseline value, with last on-treatment observation carried forward (LOCF) from Month 2 for withdrawn subjects or missing values.

Secondary Outcome Measures

Name	Time	Method
Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Month 4	Baseline and Month 4	Change from baseline was calculated as the Month 4 value minus the baseline value, with last on-treatment observation carried forward (LOCF) from Month 2 for withdrawn subjects or missing values.
Number of Subjects Achieving A1C Target at Month 12	Month 12	A1C responders were described as subjects having achieved A1C less than 7 percent at Month 12 with LOCF from Month 2.
Mean Change From Baseline in A1C at Month 4	Baseline and Month 4	Change from baseline was calculated as the Month 4 value minus the baseline value, with last on-treatment observation carried forward (LOCF) from Month 2 for withdrawn subjects or missing values.
Number of Subjects Achieving A1C Target at Month 6	Month 6	A1C responders were described as subjects having achieved A1C less than 7 percent at Month 6, with LOCF from Month 2.
Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Month 12	Baseline and Month 12	Change from baseline was calculated as the Month 12 value minus the baseline value, with LOCF from Month 2 for withdrawn subjects or missing values.
Number of Subjects Achieving FPG Target at Month 4	Month 4	FPG responders were described as subjects having achieved FPG less than 7 mmol/L at Month 4 with LOCF from Month 2.
Number of Subjects Achieving A1C Target at Month 4	Month 4	A1C responders were described as subjects having achieved A1C less than 7 percent at Month 4, with LOCF from Month 2.
Number of Subjects Achieving FPG Target at Month 6	Month 6	FPG responders were described as subjects having achieved FPG less than 7 mmol/L at Month 6 with LOCF from Month 2.
Mean Change From Baseline in A1C at Month 12	Baseline and Month 12	Change from baseline was calculated as the Month 12 value minus the baseline value, with last on-treatment observation carried forward (LOCF) from Month 2 for withdrawn subjects or missing values.
Mean Change From Baseline in C-reactive Protein (CRP) at Month 6	Baseline and Month 6	Change from baseline was calculated as the Month 6 value minus the baseline value. LOCF was not used for this analysis. CRP was only done at baseline, months 6 and 8. The test was optional and performed only by participating sites.
Mean Change From Baseline in C-reactive Protein (CRP) at Month 12	Baseline and Month 12	Change from baseline was calculated as the Month 12 value minus the baseline value, with LOCF from Month 6. CRP was only done at baseline, months 6 and 12. The test was optional and performed only by participating sites.
Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Month 6	Baseline and Month 6	Change from baseline was calculated as the Month 6 value minus the baseline value, with last on-treatment observation carried forward (LOCF) from Month 2 for withdrawn subjects or missing values.
Number of Subjects Achieving FPG Target at Month 12	Month 12	FPG responders were described as subjects having achieved FPG less than 7 mmol/L at Month 12 with LOCF from Month 2.
Mean Change From Baseline in 5 Year UKPDS Risk Scores at Month 6	Baseline and Month 6	Change from baseline was calculated as the Month 6 value minus the baseline value, with LOCF from Month 2. The UKPDS (United Kingdom Prospective Diabetes Study) risk engine calculated was based on 5 years risk using gender, race, age at diagnosis of diabetes, duration of diabetes, smoking status, A1C, systolic blood pressure and total cholesterol to high-density lipoprotein (HDL) ratio at a specified visit. The UKPDS cardiovascular disease (CVD) risk engine is used to estimate the risk of having coronary heart disease in type II diabetes according to the UKPDS model. The possible risk scores can range from 0 to 100% and hence lower scores would predict a person is less likely to have an event.
Mean Change From Baseline in 5 Year UKPDS Risk Scores at Month 12	Baseline and Month 12	Change from baseline was calculated as the Month 12 value minus the baseline value, with LOCF from Month 2. The UKPDS (U.K. Prospective Diabetes Study) risk engine calculated was based on 5 years risk using gender, race, age at diagnosis of diabetes, duration of diabetes, smoking status, A1C, systolic blood pressure and total cholesterol to HDL ratio at a specified visit. The UKPDS cardiovascular disease (CVD) risk engine is used to estimate the risk of having coronary heart disease in type II diabetes according to the UKPDS model. The possible risk scores can range from 0 to 100% and hence lower scores would predict a person is less likely to have an event.
Mean Change From Baseline in Adiponectin at Month 6	Baseline and Month 6	Change from baseline was calculated as the Month 6 value minus the baseline value. LOCF was not used for this analysis. Adiponectin was only done at baseline, months 6 and 12. The test was optional and performed only by participating sites.
Mean Change From Baseline in Adiponectin at Month 12	Baseline and Month 12	Change from baseline was calculated as the Month 12 value minus the baseline value, with LOCF from Month 6. Adiponectin was only done at baseline, months 6 and 12. The test was optional and performed only by participating sites.