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”

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.

Study Type: Interventional

Study Design: Treatment, Randomized, Open Label, Active Control, Parallel Assignment, Safety/Efficacy Study

Study Primary Completion Date: January 2008

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 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.

Intervention(s) in this Clinical Trial

• Drug: Avandia, Amaryl, Avandamet, Metformin
  • Avandamet 2/500mg BID to 4mg/1000mg BID;Avandia+Amaryl 4mg+1mg OD up to 8mg+2mg OD over 6 months or Metformin 500mg BID up to 1000mg over 6 months

Arms, Groups and Cohorts in this Clinical Trial

• Active Comparator: 1
  • Avandamet 2mg/500mg BID titration up to 4mg/1000mg BID over 6 months
• Active Comparator: 2
  • Avandia + Amaryl 4mg + 1mg OD titration up to 8mg +2mf OD over 6 months
• Active Comparator: 3
  • Metformin 500mg BID titration up to 1000mg BID over 6 months

Primary Measures

• The mean change in A1C from baseline to 6 months post-randomization
  • Time Frame: 6 months
    Safety Issue?: No

Secondary Measures

• The mean change from baseline in A1C to 4, and 12 months post-randomization,
  • Time Frame: 4 - 12 months
    Safety Issue?: No
• % of patients achieving A1C < 7% and a FPG < 7 mmol/L at 4, 6 and 12 months,
  • Time Frame: 4, 6 and 12 months
    Safety Issue?: No
• change in FPG to month 4, 6, 12,
  • Time Frame: 4, 6 and 12 months
    Safety Issue?: No
• change in QoL/HE evaluation to month 6 and 12,
  • Time Frame: 6 and 12 months
    Safety Issue?: No
• change in insulin sensitivity as measured by IS (Isotechnika) breath test and HOMA-S 6 and 12 month;
  • Time Frame: 6 and 12 months
    Safety Issue?: No
• 'homeostasis model assessment' (HOMA) (ref. 1, 2),
  • Time Frame: 12months
    Safety Issue?: No
• change in mean risk-engine score to month 6 and 12,
  • Time Frame: 6 and 12 months
    Safety Issue?: No
• change in CV biomarkers from baseline to month 6 and 12.
  • Time Frame: 6 and 12 months
    Safety Issue?: No

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:
• 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) 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

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 75 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Canadian Heart Research Centre

Overall Clinical Trial Officials and Contacts

robert josse, md Principal Investigator University of Toronto  

Information obtained from ClinicalTrials.gov on July 02, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00131664

Study ID Number: AVM103436

ClinicalTrials.gov Identifier: NCT00131664

Health Authority: Canada: Health Canada

coordinating centre web site