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.

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 glimeperimide. 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 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 guidelines, their fasting plasma glucose and A1C to be 7 (mmol/L/%) 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.

Condition	Intervention	Phase
Type 2 Diabetes Mellitus	Drug: Avandia™ , Amaryl™ , Avandamet™, Metformin  Drug: Avandia™ + Amaryl™ or Avandamet™ vs Metformin	Phase III

Further Study Details: 

Primary Outcomes: The mean change in A1C from baseline to 6 months post-randomization
Secondary Outcomes: 1. The mean change in A1C from baseline to 4, and 12 months post-randomization.; 2. % of patients achieving A1C < 7% and a FPG < 7 mmol/L from baseline to 4, 6 and 12 months post-randomization; 3. Change in FPG from baseline to month 4, 6, 12.; 4. Change in QoL/HE evaluation from baseline to month 6 and 12 post-randomization.; 5. Assessment of safety and tolerability in each treatment group over 12 months.; 6. Change in insulin sensitivity as measured by IS (Isotechnika) breath test and HOMA-S from baseline to month 6 and 12 month; ‘homeostasis model assessment’ (HOMA) (ref. 1, 2); 7. Change in mean risk-engine score from baseline to month 6 and 12.; 8. Change in CV biomarkers from baseline to month 6 and 12.
Expected Total Enrollment:  381

Ages Eligible for Study:  18 Years   -   75 Years,  Genders Eligible for Study:  Both

Criteria

Inclusion Criteria:

1. Type 2 diabetes patients 2. 18 - 75 years old 3. Type 2 DM drug naïve or on submaximal oral monotherapy < 3 years 4. A1C criteria at screening:

a. 7.1-10% for drug naïve patients after failure of diet control and life-style modification b. 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) 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 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 (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

Please refer to this study by ClinicalTrials.gov identifier  NCT00131664

anatoly langer, md      416-999-6264    langera@chrc.net
oksana kornilova      416-977-8010  Ext. 239    kornilovao@chrc.net

Canada, Ontario
      Canadian Heart Research Centre, Toronto,  Ontario,  m5b 2p9,  Canada

Study chairs or principal investigators

robert josse, md,  Principal Investigator,  University of Toronto   

Study ID Numbers:  AVM103436
Last Updated:  August 18, 2005
Record first received:  August 17, 2005
ClinicalTrials.gov Identifier:  NCT00131664
Health Authority: Canada: Health Canada
ClinicalTrials.gov processed this record on 2005-08-23