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

This study has been completed.
Sponsor:
Collaborator:
GlaxoSmithKline
Information provided by (Responsible Party):
Dr. Anatoly Langer, Canadian Heart Research Centre
ClinicalTrials.gov Identifier:
NCT00131664
First received: August 17, 2005
Last updated: April 15, 2013
Last verified: April 2013

August 17, 2005
April 15, 2013
September 2005
January 2008   (final data collection date for primary outcome measure)
Mean Change From Baseline in A1C at Month 6 [ Time Frame: Baseline and Month 6 ] [ Designated as safety issue: No ]
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the Month 6 value minus the baseline value, with last on-treatment observation carried forward (LOCF) from Month 2 for withdrawn subjects or missing values.
The mean change in A1C from baseline to 6 months post-randomization
Complete list of historical versions of study NCT00131664 on ClinicalTrials.gov Archive Site
  • Mean Change From Baseline in A1C at Month 4 [ Time Frame: Baseline and Month 4 ] [ Designated as safety issue: No ]
    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the Month 4 value minus the baseline value, with last on-treatment observation carried forward (LOCF) from Month 2 for withdrawn subjects or missing values.
  • Mean Change From Baseline in A1C at Month 12 [ Time Frame: Baseline and Month 12 ] [ Designated as safety issue: No ]
    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the Month 12 value minus the baseline value, with last on-treatment observation carried forward (LOCF) from Month 2 for withdrawn subjects or missing values.
  • Number of Subjects Achieving A1C Target at Month 4 [ Time Frame: Month 4 ] [ Designated as safety issue: No ]
    A1C responders were described as subjects having achieved A1C less than 7 percent at Month 4, with LOCF from Month 2.
  • Number of Subjects Achieving A1C Target at Month 6 [ Time Frame: Month 6 ] [ Designated as safety issue: No ]
    A1C responders were described as subjects having achieved A1C less than 7 percent at Month 6, with LOCF from Month 2.
  • Number of Subjects Achieving A1C Target at Month 12 [ Time Frame: Month 12 ] [ Designated as safety issue: No ]
    A1C responders were described as subjects having achieved A1C less than 7 percent at Month 12 with LOCF from Month 2.
  • Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Month 4 [ Time Frame: Baseline and Month 4 ] [ Designated as safety issue: No ]
    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.
  • Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Month 6 [ Time Frame: Baseline and Month 6 ] [ Designated as safety issue: No ]
    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.
  • Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Month 12 [ Time Frame: Baseline and Month 12 ] [ Designated as safety issue: No ]
    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.
  • Number of Subjects Achieving FPG Target at Month 4 [ Time Frame: Month 4 ] [ Designated as safety issue: No ]
    FPG responders were described as subjects having achieved FPG less than 7 mmol/L at Month 4 with LOCF from Month 2.
  • Number of Subjects Achieving FPG Target at Month 6 [ Time Frame: Month 6 ] [ Designated as safety issue: No ]
    FPG responders were described as subjects having achieved FPG less than 7 mmol/L at Month 6 with LOCF from Month 2.
  • Number of Subjects Achieving FPG Target at Month 12 [ Time Frame: Month 12 ] [ Designated as safety issue: No ]
    FPG responders were described as subjects having achieved FPG less than 7 mmol/L at Month 12 with LOCF from Month 2.
  • Mean Change From Baseline in 5 Year UKPDS Risk Scores at Month 6 [ Time Frame: Baseline and Month 6 ] [ Designated as safety issue: No ]

    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.

  • Mean Change From Baseline in 5 Year UKPDS Risk Scores at Month 12 [ Time Frame: Baseline and Month 12 ] [ Designated as safety issue: No ]

    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.

  • Mean Change From Baseline in C-reactive Protein (CRP) at Month 6 [ Time Frame: Baseline and Month 6 ] [ Designated as safety issue: No ]
    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.
  • Mean Change From Baseline in C-reactive Protein (CRP) at Month 12 [ Time Frame: Baseline and Month 12 ] [ Designated as safety issue: No ]
    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.
  • Mean Change From Baseline in Adiponectin at Month 6 [ Time Frame: Baseline and Month 6 ] [ Designated as safety issue: No ]
    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.
  • Mean Change From Baseline in Adiponectin at Month 12 [ Time Frame: Baseline and Month 12 ] [ Designated as safety issue: No ]
    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.
  • 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.
Not Provided
Not Provided
 
Avandia™ + Amaryl™ or Avandamet™ Compared With Metformin (AVALANCHE™ Study)
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.

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.

Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Type 2 Diabetes Mellitus
  • Drug: Avandamet
    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
  • Drug: Avandia and Amaryl
    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
  • Drug: Metformin
    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
  • Active Comparator: Avandamet
    Avandamet 2 mg / 500 mg twice daily titration up to 4 mg / 1000 mg twice daily over 6 months
    Intervention: Drug: Avandamet
  • 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
    Intervention: Drug: Avandia and Amaryl
  • Active Comparator: Metformin
    Metformin 500 mg twice daily titration up to 1000 mg twice daily over 6 months
    Intervention: Drug: Metformin
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
391
January 2008
January 2008   (final data collection date for primary outcome measure)

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
Both
18 Years to 75 Years
No
Contact information is only displayed when the study is recruiting subjects
Canada
 
NCT00131664
AVM103436
Yes
Dr. Anatoly Langer, Canadian Heart Research Centre
Canadian Heart Research Centre
GlaxoSmithKline
Principal Investigator: robert josse, md University of Toronto
Canadian Heart Research Centre
April 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP