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

April 15, 2013 updated by: Dr. Anatoly Langer, Canadian Heart Research Centre

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 Overview

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.

Study Type

Interventional

Enrollment (Actual)

391

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

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

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 75 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
ACTIVE_COMPARATOR: Avandamet
Avandamet 2 mg / 500 mg twice daily titration up to 4 mg / 1000 mg twice daily over 6 months
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.
Other Names:
  • rosiglitazone maleate and metformin hydrochloride
  • Avandamet 2 mg / 500 mg
  • Avandamet 4 mg / 500 mg
  • Avandamet 4 mg / 1000 mg
ACTIVE_COMPARATOR: Avandia and Amaryl
Avandia + Amaryl 4 mg + 1 mg once daily titration up to 8 mg + 2 mg once daily over 6 months
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.
Other Names:
  • rosiglitazone maleate and glimepiride
  • Avandia (rosiglitazone maleate) 4 mg
  • Avandia (rosiglitazone maleate) 8 mg
  • Amaryl (glimepiride) 1 mg
  • Amaryl (glimepiride) 2 mg
  • Amaryl (glimepiride) 4 mg
ACTIVE_COMPARATOR: Metformin
Metformin 500 mg twice daily titration up to 1000 mg twice daily over 6 months
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
Other Names:
  • Metformin 500 mg
  • Metformin 850 mg

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Mean Change From Baseline in A1C at Month 4
Time Frame: 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.
Baseline and Month 4
Mean Change From Baseline in A1C at Month 12
Time Frame: 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.
Baseline and Month 12
Number of Subjects Achieving A1C Target at Month 4
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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.
Baseline and Month 4
Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Month 6
Time Frame: 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.
Baseline and Month 6
Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Month 12
Time Frame: 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.
Baseline and Month 12
Number of Subjects Achieving FPG Target at Month 4
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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.

Baseline and Month 6
Mean Change From Baseline in 5 Year UKPDS Risk Scores at Month 12
Time Frame: 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.

Baseline and Month 12
Mean Change From Baseline in C-reactive Protein (CRP) at Month 6
Time Frame: 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.
Baseline and Month 6
Mean Change From Baseline in C-reactive Protein (CRP) at Month 12
Time Frame: 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.
Baseline and Month 12
Mean Change From Baseline in Adiponectin at Month 6
Time Frame: 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.
Baseline and Month 6
Mean Change From Baseline in Adiponectin at Month 12
Time Frame: 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.
Baseline and Month 12

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Collaborators

Investigators

  • Principal Investigator: robert josse, md, University of Toronto

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

September 1, 2005

Primary Completion (ACTUAL)

January 1, 2008

Study Completion (ACTUAL)

January 1, 2008

Study Registration Dates

First Submitted

August 17, 2005

First Submitted That Met QC Criteria

August 17, 2005

First Posted (ESTIMATE)

August 19, 2005

Study Record Updates

Last Update Posted (ESTIMATE)

April 17, 2013

Last Update Submitted That Met QC Criteria

April 15, 2013

Last Verified

April 1, 2013

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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