Clinical trial NCT00131664: Avandia™ + Amaryl™ or Avandamet™ Compared With Metformin (AVALANCHE™ Study)
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Type 2 Diabetes Mellitus
Lead sponsor: Canadian Heart Research Centre
Sponsor class: OTHER
Collaborators: name: GlaxoSmithKline
First posted: 2005-08-19
Enrollment: 391
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

1. Type 2 diabetes patients
2. 18 - 75 years old
3. Type 2 diabetes mellitus (DM) drug naïve or on submaximal oral monotherapy \< 3 years
4. 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
5. Signed informed consent

Exclusion Criteria:

1. Type 1 diabetes
2. Subjects currently treated with insulin
3. Subject treated for previous 3 month with any thiazolidinedione (TZD)
4. 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
5. Subjects who have hypersensitivity to any components of study drugs
6. Participation in a clinical trial and/or intake of an investigational drug within 30 days prior to screening.
7. Pregnant or nursing females
8. Females of childbearing potential who are not on adequate birth control
9. Liver enzymes (Alanine Aminotransferase (ALT) \> 2.5 times upper limit of normal)
10. Renal impairment: serum creatinine ≥ 136umol/L (males) and ≥ 124 umol/L (females)
11. Congestive Heart Failure (CHF class III/IV)
12. Weight \>160 kg

Primary outcomes:
measure: Mean Change From Baseline in A1C at Month 6
timeFrame: Baseline and Month 6
Secondary outcomes:
measure: Mean Change From Baseline in A1C at Month 4
timeFrame: Baseline and Month 4
measure: Mean Change From Baseline in A1C at Month 12
timeFrame: Baseline and Month 12
measure: Number of Subjects Achieving A1C Target at Month 4
timeFrame: Month 4
measure: Number of Subjects Achieving A1C Target at Month 6
timeFrame: Month 6
measure: Number of Subjects Achieving A1C Target at Month 12
timeFrame: Month 12
measure: Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Month 4
timeFrame: Baseline and Month 4
measure: Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Month 6
timeFrame: Baseline and Month 6
measure: Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Month 12
timeFrame: Baseline and Month 12
measure: Number of Subjects Achieving FPG Target at Month 4
timeFrame: Month 4
measure: Number of Subjects Achieving FPG Target at Month 6
timeFrame: Month 6
measure: Number of Subjects Achieving FPG Target at Month 12
timeFrame: Month 12
measure: Mean Change From Baseline in 5 Year UKPDS Risk Scores at Month 6
timeFrame: Baseline and Month 6
measure: Mean Change From Baseline in 5 Year UKPDS Risk Scores at Month 12
timeFrame: Baseline and Month 12
measure: Mean Change From Baseline in C-reactive Protein (CRP) at Month 6
timeFrame: Baseline and Month 6
measure: Mean Change From Baseline in C-reactive Protein (CRP) at Month 12
timeFrame: Baseline and Month 12
measure: Mean Change From Baseline in Adiponectin at Month 6
timeFrame: Baseline and Month 6
measure: Mean Change From Baseline in Adiponectin at Month 12
timeFrame: Baseline and Month 12
Other outcomes:
Locations:
city: Toronto
country: Canada
facility: Canadian Heart Research Centre
state: Ontario
Study officials:
affiliation: University of Toronto
name: robert josse, md
role: PRINCIPAL_INVESTIGATOR
References: