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

Study Overview
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Brief Summary
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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
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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.

Official Title
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Avandia™ + Amaryl™ or Avandamet™ Compared With Metformin: A 48-week Randomized, Open-label, Multicentre Phase IIIB Study to Compare the Effectiveness of Combination Therapy to Monotherapy in Type 2 Diabetes Mellitus Patients

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Avandamet
* Drug: Avandia and Amaryl
* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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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: 7.1-10% for drug naïve patients after failure of diet control and life-style modification 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Avandamet<br>Avandamet 2 mg / 500 mg twice daily titration up to 4 mg / 1000 mg twice daily over 6 months | Drug: Avandamet<br>* Avandamet 2 / 500 mg twice daily titration up to 4 mg / 1000 mg twice daily compared to Avandia 4 mg and Amaryl 1 mg once daily over 6 months or compared to Metformin 500 mg twice daily up to 1000 mg over 6 months.<br>* Other names: Avandamet 4 mg / 1000 mg;|
| Active Comparator: Avandia and Amaryl<br>Avandia + Amaryl 4 mg + 1 mg once daily titration up to 8 mg + 2 mg once daily over 6 months | Drug: Avandia and Amaryl<br>* Avandia 4 mg and Amaryl 1 mg once daily compared to Avandamet 2 / 500 mg twice daily titration up to 4 mg / 1000 mg twice daily, or compared to Metformin 500 mg twice daily up to 1000 mg over 6 months.<br>* Other names: Amaryl (glimepiride) 4 mg;|
| Active Comparator: Metformin<br>Metformin 500 mg twice daily titration up to 1000 mg twice daily over 6 months | Drug: Metformin<br>* Metformin 500 mg twice daily up to 1000 mg over 6 months compared to Avandia 4 mg and Amaryl 1 mg once daily or compared to Avandamet 2 / 500 mg twice daily titration up to 4 mg / 1000 mg twice daily<br>* Other names: Metformin 850 mg;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in A1C at 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. | Baseline and Month 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in A1C at 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. | Baseline and Month 4 | 
| Mean Change From Baseline in A1C at 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. | Baseline and Month 12 | 
| Number of Subjects Achieving A1C Target at Month 4 | A1C responders were described as subjects having achieved A1C less than 7 percent at Month 4, with LOCF from Month 2. | Month 4 | 
| Number of Subjects Achieving A1C Target at Month 6 | A1C responders were described as subjects having achieved A1C less than 7 percent at Month 6, with LOCF from Month 2. | Month 6 | 
| Number of Subjects Achieving A1C Target at Month 12 | A1C responders were described as subjects having achieved A1C less than 7 percent at Month 12 with LOCF from Month 2. | Month 12 | 
| Mean Change From Baseline in Fasting Plasma Glucose (FPG) at 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. | Baseline and Month 4 | 
| Mean Change From Baseline in Fasting Plasma Glucose (FPG) at 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. | Baseline and Month 6 | 
| Mean Change From Baseline in Fasting Plasma Glucose (FPG) at 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. | Baseline and Month 12 | 
| Number of Subjects Achieving FPG Target at Month 4 | FPG responders were described as subjects having achieved FPG less than 7 mmol/L at Month 4 with LOCF from Month 2. | Month 4 | 
| Number of Subjects Achieving FPG Target at Month 6 | FPG responders were described as subjects having achieved FPG less than 7 mmol/L at Month 6 with LOCF from Month 2. | Month 6 | 
| Number of Subjects Achieving FPG Target at Month 12 | FPG responders were described as subjects having achieved FPG less than 7 mmol/L at Month 12 with LOCF from Month 2. | Month 12 | 
| Mean Change From Baseline in 5 Year UKPDS Risk Scores at 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. | Baseline and Month 6 | 
| Mean Change From Baseline in 5 Year UKPDS Risk Scores at 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. | Baseline and Month 12 | 
| Mean Change From Baseline in C-reactive Protein (CRP) at 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. | Baseline and Month 6 | 
| Mean Change From Baseline in C-reactive Protein (CRP) at 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. | Baseline and Month 12 | 
| Mean Change From Baseline in Adiponectin at 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. | Baseline and Month 6 | 
| Mean Change From Baseline in Adiponectin at 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. | Baseline and Month 12 |